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  • 1.
    Almgren, Malin
    et al.
    Karolinska Institutet.
    Nyengaard, Jens R
    Aarhus University.
    Persson, Bengt
    Linköpings universitet, Tekniska högskolan. Linköpings universitet, Institutionen för fysik, kemi och biologi, Bioinformatik.
    Lavebratt, Catharina
    Karolinska Institutet.
    Carbamazepine protects against neuronal hyperplasia and abnormal gene expression in the megencephaly mouse2008Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 32, s. 364-376Artikel i tidskrift (Refereegranskat)
  • 2. Andersson, M
    et al.
    Hilbertson, A
    Cenci, M A
    Striatal fosB expression is causally linked with l-DOPA-induced abnormal involuntary movements and the associated upregulation of striatal prodynorphin mRNA in a rat model of Parkinson's disease.1999Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 6, nr 6, s. 461-74Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Rats with unilateral dopamine-denervating lesions sustained a 3-week treatment with a daily l-DOPA dose that is in the therapeutic range for Parkinson's disease. In most of the treated animals, chronic l-DOPA administration gradually induced abnormal involuntary movements affecting cranial, trunk, and limb muscles on the side of the body contralateral to the lesion. This effect was paralleled by an induction of FosB-like immunoreactive proteins in striatal subregions somatotopically related to the types of movements that had been elicited by l-DOPA. The induced proteins showed both regional and cellular colocalization with prodynorphin mRNA. Intrastriatal infusion of fosB antisense inhibited the development of dyskinetic movements that were related to the striatal subregion targeted and produced a local specific downregulation of prodynorphin mRNA. These data provide compelling evidence of a causal role for striatal fosB induction in the development of l-DOPA-induced dyskinesia in the rat and of a positive regulation of prodynorphin gene expression by FosB-related transcription factors.

  • 3.
    Annelies, Nonneman
    et al.
    KU Leuven Univ Leuven, Dept Neurosci, Lab Neurobiol & Expt Neurol, Herestr 49, B-3000 Leuven, Belgium.;LBI, Herestr 49, B-3000 Leuven, Belgium.;Ctr Brain & Dis Res, VIB, Herestr 49, B-3000 Leuven, Belgium..
    Nathan, Criem
    Ctr Brain & Dis Res, VIB, Herestr 49, B-3000 Leuven, Belgium.;KU Leuven Univ Leuven, Dept Cardiovasc Sci, Ctr Mol & Vasc Biol, Herestr 49, B-3000 Leuven, Belgium.;KU Leuven Univ Leuven, Dept Human Genet, Herestr 49, B-3000 Leuven, Belgium..
    Lewandowski, Sebastian
    KTH, Skolan för kemi, bioteknologi och hälsa (CBH), Proteinvetenskap, Affinity Proteomics. KTH, Centra, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Clin Neurosci, S-17177 Stockholm, Sweden..
    Rik, Nuyts
    KU Leuven Univ Leuven, Dept Neurosci, Lab Neurobiol & Expt Neurol, Herestr 49, B-3000 Leuven, Belgium.;LBI, Herestr 49, B-3000 Leuven, Belgium.;Ctr Brain & Dis Res, VIB, Herestr 49, B-3000 Leuven, Belgium..
    Dietmar, Thal R.
    KU Leuven Univ Leuven, Dept Neurosci, Lab Neuropathol, Herestr 49, B-3000 Leuven, Belgium.;Univ Hosp Leuven, Dept Neurol, Herestr 49, B-3000 Leuven, Belgium..
    Frank, Pfrieger W.
    Univ Strasbourg, CNRS UPR 3212, Inst Cellular & Integrat Neurosci, F-67084 Strasbourg, France..
    John, Ravits
    Univ Calif San Diego, Dept Neurosci, 9500 Gilman Dr, San Diego, CA 92093 USA..
    Philip, Van Damme
    KU Leuven Univ Leuven, Dept Neurosci, Lab Neurobiol & Expt Neurol, Herestr 49, B-3000 Leuven, Belgium.;LBI, Herestr 49, B-3000 Leuven, Belgium.;Ctr Brain & Dis Res, VIB, Herestr 49, B-3000 Leuven, Belgium.;Univ Hosp Leuven, Dept Neurol, Herestr 49, B-3000 Leuven, Belgium..
    An, Zwijsen
    Ctr Brain & Dis Res, VIB, Herestr 49, B-3000 Leuven, Belgium.;KU Leuven Univ Leuven, Dept Cardiovasc Sci, Ctr Mol & Vasc Biol, Herestr 49, B-3000 Leuven, Belgium.;KU Leuven Univ Leuven, Dept Human Genet, Herestr 49, B-3000 Leuven, Belgium..
    Ludo, Van Den Bosch
    KU Leuven Univ Leuven, Dept Neurosci, Lab Neurobiol & Expt Neurol, Herestr 49, B-3000 Leuven, Belgium.;LBI, Herestr 49, B-3000 Leuven, Belgium.;Ctr Brain & Dis Res, VIB, Herestr 49, B-3000 Leuven, Belgium..
    Wim, Robberecht
    KU Leuven Univ Leuven, Dept Neurosci, Lab Neurobiol & Expt Neurol, Herestr 49, B-3000 Leuven, Belgium.;LBI, Herestr 49, B-3000 Leuven, Belgium.;Ctr Brain & Dis Res, VIB, Herestr 49, B-3000 Leuven, Belgium.;Univ Hosp Leuven, Dept Neurol, Herestr 49, B-3000 Leuven, Belgium..
    Astrocyte-derived Jagged-1 mitigates deleterious Notch signaling in amyotrophic lateral sclerosis2018Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 119, s. 26-40Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Amyotrophic lateral sclerosis (ALS) is a late-onset devastating degenerative disease mainly affecting motor neurons. Motor neuron degeneration is accompanied and aggravated by oligodendroglial pathology and the presence of reactive astrocytes and microglia. We studied the role of the Notch signaling pathway in ALS, as it is implicated in several processes that may contribute to this disease, including axonal retraction, microgliosis, astrocytosis, oligodendrocyte precursor cell proliferation and differentiation, and cell death. We observed abnormal activation of the Notch signaling pathway in the spinal cord of SOD1(G93A) mice, a well-established model for ALS, as well as in the spinal cord of patients with sporadic ALS (sALS). This increased activation was particularly evident in reactive GFAP-positive astrocytes. In addition, one of the main Notch ligands, Jagged-1, was ectopically expressed in reactive astrocytes in spinal cord from ALS mice and patients, but absent in resting astrocytes. Astrocyte-specific inactivation of Jagged-1 in presymptomatic SOD1(G93A) mice further exacerbated the activation of the Notch signaling pathway and aggravated the course of the disease in these animals without affecting disease onset. These data suggest that aberrant Notch signaling activation contributes to the pathogenesis of ALS, both in sALS patients and SOD1(G93A) mice, and that it is mitigated in part by the upregulation of astrocytic Jagged-1.

  • 4. Bourdenx, Mathieu
    et al.
    Nilsson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Wadensten, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Fälth, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Li, Qin
    Crossman, Alan R.
    Andrén, Per E.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för farmaceutisk biovetenskap.
    Bezard, Erwan
    Abnormal structure-specific peptide transmission and processing in a primate model of Parkinson's disease and L-DOPA-induced dyskinesia2014Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 62, s. 307-312Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A role for enhanced peptidergic transmission, either opioidergic or not, has been proposed for the generation of L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) on the basis of in situ hybridization studies showing that striatal peptidergic precursor expression consistently correlates with LID severity. Few studies, however, have focused on the actual peptides derived from these precursors. We used mass-spectrometry to study peptide profiles in the putamen and globus pallidus (internalis and externalis) collected from 1-methyl-4-phenyl-1,2,4,6-tetrahydropyridine treated macaque monkeys, acutely or chronically treated with L-DOPA. We identified that parkinsonian and dyskinetic states are associated with an abnormal production of proenkephalin-, prodynorphin- and protachykinin-1-derived peptides in both segments of the globus pallidus. Moreover, we report that peptidergic processing is dopamine-state dependent and highly structure-specific, possibly explaining the failure of previous clinical trials attempting to rectify abnormal peptidergic transmission.

  • 5.
    Domert, Jakob
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Rao, Sahana Bhima
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Agholme, Lotta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Brorsson, Ann-Christin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Kemi. Linköpings universitet, Tekniska högskolan.
    Marcusson, Jan
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neurovetenskap. Linköpings universitet, Hälsouniversitetet.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk patologi och klinisk genetik.
    Nath, Sangeeta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet.
    Spreading of Amyloid-β Peptides via Neuritic Cell-to-cell Transfer Is Dependent on Insufficient Cellular Clearance2014Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 65, s. 82-92Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The spreading of pathology through neuronal pathways is likely to be the cause of the progressive cognitive loss observed in Alzheimer's disease (AD) and other neurodegenerative diseases. We have recently shown the propagation of AD pathology via cell-to-cell transfer of oligomeric amyloid beta (Aβ) residues 1-42 (oAβ1-42) using our donor-acceptor 3-D co-culture model. We now show that different Aβ-isoforms (fluorescently labeled 1-42, 3(pE)-40, 1-40 and 11-42 oligomers) can transfer from one cell to another. Thus, transfer is not restricted to a specific Aβ-isoform. Although different Aβ isoforms can transfer, differences in the capacity to clear and/or degrade these aggregated isoforms result in vast differences in the net amounts ending up in the receiving cells and the net remaining Aβ can cause seeding and pathology in the receiving cells. This insufficient clearance and/or degradation by cells creates sizable intracellular accumulations of the aggregation-prone Aβ1-42 isoform, which further promotes cell-to-cell transfer; thus, oAβ1-42 is a potentially toxic isoform. Furthermore, cell-to-cell transfer is shown to be an early event that is seemingly independent of later appearances of cellular toxicity. This phenomenon could explain how seeds for the AD pathology could pass on to new brain areas and gradually induce AD pathology, even before the first cell starts to deteriorate, and how cell-to-cell transfer can act together with the factors that influence cellular clearance and/or degradation in the development of AD.

  • 6.
    Emilsson, Lina
    et al.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Zoologisk utvecklingsbiologi.
    Saetre, Peter
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Zoologisk utvecklingsbiologi.
    Jazin, Elena
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för fysiologi och utvecklingsbiologi, Zoologisk utvecklingsbiologi.
    Alzheimer’s disease: mRNA expression profiles of multiple patients show alterations of genes involved with calcium signalling2006Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 21, nr 3, s. 618-625Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We combined global and high-resolution strategies to find genes with altered mRNA expression levels in one of the largest collection of brain autopsies from Alzheimer's patients and controls ever studied. Our global analysis involved microarray hybridizations of large pools of samples obtained from 114 individuals, using two independent sets of microarrays. Ten genes selected from the microarray experiments were quantified on each individual separately using real-time RT-PCR. This high-resolution analysis accounted for systematic differences in age, postmortem interval, brain pH, and reference gene expression, and it estimated the effect of disease on mRNA levels, on top of the effect of all other variables. Differential expression was confirmed for eight out of ten genes. Among them, Type B inositol 1,4,5-trisphosphate 3-kinase (ITPKB), and regulator of G protein signaling 4 (RGS4) showed highly altered expression levels in patients (P values < 0.0001). Our results point towards increased inositol triphospate (IP3)-mediated calcium signaling in Alzheimer's disease.

  • 7. Farias, Fabiana H. G.
    et al.
    Zeng, Rong
    Johnson, Gary S.
    Wininger, Fred A.
    Taylor, Jeremy F.
    Schnabel, Robert D.
    McKay, Stephanie D.
    Sanders, Douglas N.
    Lohi, Hannes
    Seppälä, Eija H.
    Wade, Claire M.
    Lindblad-Toh, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    O'Brien, Dennis P.
    Katz, Martin L.
    A truncating mutation in ATP13A2 is responsible for adult-onset neuronal ceroid lipofuscinosis in Tibetan terriers2011Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 42, nr 3, s. 468-474Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A recessive, adult-onset neuronal ceroid-lipofuscinosis (NCL) occurs in Tibetan terriers. A genome-wide association study restricted this NCL locus to a 1.3 Mb region of canine chromosome 2 which contains canine ATP13A2. NCL-affected dogs were homozygous for a single-base deletion in ATP13A2, predicted to produce a frameshift and premature termination codon. Homozygous truncating mutations in human ATP13A2 have been shown by others to cause Kufor-Rakeb syndrome (KRS), a rare neurodegenerative disease. These findings suggest that KRS is also an NCL, although analysis of KRS brain tissue will be needed to confirm this prediction. Generalized brain atrophy, behavioral changes, and cognitive decline occur in both people and dogs with ATP13A2 mutations: however, other clinical features differ between the species. For example, Tibetan terriers with NCL develop cerebellar ataxia not reported in KRS patients and KRS patients exhibit parkinsonism and pyramidal dysfunction not observed in affected Tibetan terriers. To see if ATP13A2 mutations could be responsible for some cases of human adult-onset NCL (Kufs disease), we resequenced ATP13A2 from 28 Kufs disease patients. None of these patients had ATP13A2 sequence variants likely to be causal for their disease, suggesting that mutations in this gene are not common causes of Kufs disease.

  • 8. Gispert, Suzana
    et al.
    Kurz, Alexander
    Waibel, Stefan
    Bauer, Peter
    Liepelt, Inga
    Geisen, Christof
    Gitler, Aaron D.
    Becker, Tim
    Weber, Markus
    Berg, Daniela
    Andersen, Peter M.
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Krueger, Rejko
    Riess, Olaf
    Ludolph, Albert C.
    Auburger, Georg
    The modulation of Amyotrophic Lateral Sclerosis risk by Ataxin-2 intermediate polyglutamine expansions is a specific effect2012Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 45, nr 1, s. 356-361Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Full expansions of the polyglutamine domain (polyQ >= 34) within the polysome-associated protein ataxin-2 (ATXN2) are the cause of a multi-system neurodegenerative disorder, which usually presents as a Spino-Cerebellar Ataxia and is therefore known as SCA2, but may rarely manifest as Levodopa-responsive Parkinson syndrome or as motor neuron disease. Intermediate expansions (27 <= polyQ <= 33) were reported to modify the risk of Amyotrophic Lateral Sclerosis (ALS). We have now tested the reproducibility and the specificity of this observation. In 559 independent ALS patients from Central Europe, the association of ATXN2 expansions (30 <= polyQ <= 35) with ALS was highly significant. The study of 1490 patients with Parkinson's disease (PD) showed an enrichment of ATXN2 alleles 27/28 in a subgroup with familial cases, but the overall risk of sporadic PD was unchanged. No association was found between polyQ expansions in Ataxin-3 (ATXN3) and ALS risk. These data indicate a specific interaction between ATXN2 expansions and the causes of ALS, possibly through altered RNA-processing as a common pathogenic factor. (C) 2011 Elsevier Inc. All rights reserved.

  • 9.
    Helmfors, Linda
    et al.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska fakulteten.
    Boman, Andrea
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Civitelli, Livia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Nath, Sangeeta
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Sandin, Linnea
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Janefjord, Camilla
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    McCann, Heather
    Neuroscience Research Australia and University of New South Wales, Australia.
    Zetterberg, Henrik
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden / UCL Institute of Neurology, Queen Square, London, United Kingdom.
    Blennow, Kaj
    Clinical Neurochemistry Laboratory, Department of Neuroscience and Physiology, Sahlgrenska University Hospital, Mölndal, Sweden.
    Halliday, Glenda
    UCL Institute of Neurology, Queen Square, London, United Kingdom.
    Brorsson, Ann-Christin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Molekylär Bioteknik. Linköpings universitet, Tekniska fakulteten.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Protective properties of lysozyme on β-amyloid pathology: implications for Alzheimer disease2015Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 83, s. 122-133Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The hallmarks of Alzheimer disease are amyloid-β plaques and neurofibrillary tangles accompanied by signs of neuroinflammation. Lysozyme is a major player in the innate immune system and has recently been shown to prevent the aggregation of amyloid-β1-40 in vitro. In this study we found that patients with Alzheimer disease have increased lysozyme levels in the cerebrospinal fluid and lysozyme co-localized with amyloid-β in plaques. In Drosophila neuronal co-expression of lysozyme and amyloid-β1-42 reduced the formation of soluble and insoluble amyloid-β species, prolonged survival and improved the activity of amyloid-β1-42 transgenic flies. This suggests that lysozyme levels rise in Alzheimer disease as a compensatory response to amyloid-β increases and aggregation. In support of this, in vitro aggregation assays revealed that lysozyme associates with amyloid-β1-42 and alters its aggregation pathway to counteract the formation of toxic amyloid-β species. Overall, these studies establish a protective role for lysozyme against amyloid-β associated toxicities and identify increased lysozyme in patients with Alzheimer disease. Therefore, lysozyme has potential as a new biomarker as well as a therapeutic target for Alzheimer disease.

  • 10.
    Hu, Z.
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Ulfendahl, M.
    Karolinska Institute, Stockholm, Sweden.
    Olivius, Petri
    Karolinska Institute/Karolinska University Hospital, Stockholm, Sweden .
    NGF stimulates extensive neurite outgrowth from implanted dorsal root ganglion neurons following transplantation into the adult rat inner ear2005Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 18, nr 1, s. 184-192Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Neuronal tissue transplantation is a potential way to replace degenerated spiral ganglion neurons (SGNs) since these cells cannot regenerate in adult mammals. To investigate whether nerve growth factor (NGF) can stimulate neurite outgrowth from implanted neurons, mouse embryonic dorsal root ganglion (DRG) cells expressing enhanced green fluorescent protein (EGFP) were transplanted into the scala tympani of adult rats with a supplement of NGF or artificial perilymph. DRG neurons were observed in the cochlea for up to 6 weeks postoperatively. A significant difference was identified in the number of DRG neurons between the NGF and non-NGF groups. In the NGF group, extensive neurite projections from DRGs were found penetrating the osseous modiolus towards the spiral ganglion. These results suggest the possibility that embryonic neuronal implants may become integrated within the adult auditory nervous system. In combination with a cochlear prosthesis, a neuronal implantation strategy may provide a possibility for further treatment of profoundly deaf patients.

  • 11. Johansson, P A
    et al.
    Andersson, M
    Andersson, K E
    Cenci, M A
    Alterations in cortical and basal ganglia levels of opioid receptor binding in a rat model of l-DOPA-induced dyskinesia.2001Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 8, nr 2, s. 220-39Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Opioid receptor-binding autoradiography was used as a way to map sites of altered opioid transmission in a rat model of l-DOPA-induced dyskinesia. Rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal pathways sustained a 3-week treatment with l-DOPA (6 mg/kg/day, combined with 12 mg/kg/day benserazide), causing about half of them to develop dyskinetic-like movements on the side of the body contralateral to the lesion. Autoradiographic analysis of mu-, delta-, and kappa-opioid binding sites was carried out in the caudate-putamen (CPu), the globus pallidus (GP), the substantia nigra (SN), the primary motor area, and the premotor-cingulate cortex. The dopamine-denervating lesion alone caused an ipsilateral reduction in opioid radioligand binding in the CPu, GP, and SN, but not in the cerebral cortex. Chronic l-DOPA treatment affected opioid receptor binding in both the basal ganglia and the cerebral cortex, producing changes that were both structure- and receptor-type specific, and closely related to the motor response elicited by the treatment. In the basal ganglia, the most clear-cut differences between dyskinetic and nondyskinetic rats pertained to kappa opioid sites. On the lesioned side, both striatal and nigral levels of kappa binding densities were significantly lower in the dyskinetic group, showing a negative correlation with the rats' dyskinesia scores on one hand and with the striatal expression of opioid precursor mRNAs on the other hand. In the cerebral cortex, levels of mu and delta binding site densities were bilaterally elevated in the dyskinetic group, whereas kappa radioligand binding was specifically increased in the nondyskinetic cases and showed a negative correlation with the rats' dyskinesia scores. These data demonstrate that bilateral changes in cortical opioid transmission are closely associated with l-DOPA-induced dyskinesia in the rat. Moreover, the fact that dyskinetic and nondyskinetic animals often show opposite changes in opioid radioligand binding suggests that the motor response to l-DOPA is determined, at least in part, by compensatory adjustments of brain opioid receptors.

  • 12.
    Jonsson, P Andreas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Bäckstrand, Åsa
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Jacobsson, Johan
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurovetenskap.
    Parton, Matthew
    Shaw, Chris
    Swingler, Robert
    Shaw, Pamela J
    Robberecht, Wim
    Ludolph, Albert C
    Siddique, Teepu
    Skvortsova, Veronica I
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    CuZn-superoxide dismutase in D90A heterozygotes from recessive and dominant ALS pedigrees.2002Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 10, nr 3, s. 327-333Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mutations in CuZn-superoxide dismutase (CuZn-SOD) have been linked to ALS. In most cases ALS is inherited as a dominant trait and there is marked reduction in CuZn-SOD activity in samples from the patients. The D90A mutation, however, mostly causes ALS as a recessive trait and shows near normal CuZn-SOD activity. A few familial and sporadic ALS cases heterozygous for the D90A mutation have also been found. Haplotype analysis of both types of D90A families has suggested that all recessive cases share a common founder and may carry a protective factor located close to the D90A mutant CuZn-SOD locus. To search for effects of a putative protective factor we analysed erythrocytes from D90A heterozygous individuals for SOD activity by a direct assay, subunit composition by immunoblotting, and zymogram pattern formed by isoelectric focusing and SOD staining. Included were heterozygotes from 17 recessive families, and from 2 dominant families and 4 apparently sporadic cases. The CuZn-SOD activity in the recessive and dominant groups was found to be equal, and 95% of controls. The ratio between mutant and wildtype subunits was likewise equal and 0.8:1 in both groups. The zymograms revealed multiple bands representing homo- and heterodimers. There were, however, no differences between the groups in patterns or in ratios between the molecular forms. In conclusion we find no evidence from analyses in erythrocytes that the putative protective factor in recessive families acts by simply downregulating the synthesis or altering the molecular structure or turnover of the mutant enzyme.

  • 13.
    Jonsson, P Andreas
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Graffmo, Karin S
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Andersen, Peter M
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Neurologi.
    Marklund, Stefan L
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Brännström, Thomas
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Patologi.
    Superoxide dismutase in amyotrophic lateral sclerosis patients homozygous for the D90A mutation2009Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 36, nr 3, s. 421-424Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The most common of the amyotrophic lateral sclerosis (ALS)-associated superoxide dismutase-1 (SOD1) mutations, D90A, differs from others in its high structural stability and by the existence of both recessive and dominant inheritance. Here SOD1 in CNS and peripheral organs from five ALS patients homozygous for D90A were compared to controls. In most areas, including ventral horns, there were no significant differences in SOD1 activities and Western blotting patterns between controls and D90A cases. The SOD1 activities in areas vulnerable to mutant SOD1s, ventral horns and precentral gyrus were intermediate among CNS areas and much lower than in kidney and liver. Thus, the vulnerability of motor areas is not explained by high SOD1 content. The findings argue against the idea of expression-reducing protective factors being present near the D90A locus in recessive pedigrees. The similarity to wild-type SOD1 prompts speculations on the involvement of the latter in sporadic ALS.

  • 14. Kankaanpää, Jari
    et al.
    Turunen, S Pauliina
    Moilanen, Virpi
    Hörkkö, Sohvi
    Remes, Anne M
    Cerebrospinal fluid antibodies to oxidized LDL are increased in Alzheimer's disease.2009Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 33, nr 3, s. 467-72Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Lipoprotein oxidation may play an important role in the pathogenesis of Alzheimer's Disease (AD), and therefore, we investigated cerebrospinal fluid (CSF) antibodies to oxidized low-density lipoprotein (OxLDL) in patients with AD and other neurodegenerative dementias. IgM and IgG antibody titers to OxLDL were measured in 50 CSF samples and 11 plasma samples using chemiluminescent ELISA. All CSF samples contained IgG antibodies, and also most IgM, binding to OxLDL. CSF antibodies to OxLDL were not related to CSF protein or albumin concentrations or plasma antibodies to OxLDL. Competition immunoassay for specificity demonstrated that about 50% of the CSF IgG binding to OxLDL was inhibited by soluble OxLDL. CSF IgG antibodies to OxLDL were significantly increased in AD patients compared to controls and to patients with frontotemporal lobar degeneration. The role of these antibodies in CSF is unknown and further investigations are needed.

  • 15.
    Larsson, Elin
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Kuma, Regina
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Norberg, Anna
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Minde, Jan
    Department of Orthopedics, Gällivare Hospital, Gällivare, Sweden.
    Holmberg, Monica
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Nerve growth factor R221W responsible for insensitivity to pain is defectively processed and accumulates as proNGF2009Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 33, nr 2, s. 221-228Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We have previously identified a homozygous missense (R221W) mutation in the NGFB gene in patients with loss of deep pain perception. NGF is important not only for the survival of sensory neurons but also for the sympathetic neurons and cholinergic neurons of the basal forebrain; however, it is the sensory neurons that are mainly affected in patients with mutant NGFB. In this report, we describe the effects of the mutation on the function of NGF protein and the molecular mechanisms that may underlie the pain insensitivity phenotype in these patients. We show that the mutant NGF has lost its ability to mediate differentiation of PC12 cells into a neuron-like phenotype. We also show that the inability of PC12 cells to differentiate is due to a markedly reduced secretion of mature R221W NGF. The R221W NGF is found mainly as proNGF, in contrast to wild-type NGF which is predominantly in the mature form in both undifferentiated and differentiated PC12 cells. The reduction in numbers of sensory fibers observed in the patients is therefore probably due to loss of trophic support as a result of drastically reduced secretion of NGF from the target organs. Taken together, these data show a clear decrease in the availability of mutant mature NGF and also an accumulation of proNGF in both neuronal and non-neuronal cells. The differential loss of NGF-dependent neurons in these patients, mainly affecting sensory neurons, may depend on differences in the roles of mature NGF and proNGF in different cells and tissues.

  • 16. Lindblad, K
    et al.
    Nylander, P O
    De bruyn, A
    Sourey, D
    Zander, C
    Engström, C
    Holmgren, G
    Hudson, T
    Chotai, Jayanti
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Psykiatri.
    Mendlewicz, J
    Detection of expanded CAG repeats in bipolar affective disorder using the repeat expansion detection (RED) method.1995Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 2, nr 1, s. 55-62Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Genetic factors are of major aetiological importance in Bipolar Affective Disorder (BPAD type I and II). The exact mode of inheritance of BPAD is unknown, but the recent demonstration of anticipation suggests that dynamic mutations could be involved in the clinical expression of the disease. We have used the repeat expansion detection (RED) method to test whether the anticipation in BPAD could be explained by the presence of expanded trinucleotide repeat sequences. Using a (CTG)10 oligonucleotide a significantly higher number of expanded CAG repeats were found in the genomic DNA of two independent samples of unrelated BPAD patients of Swedish and Belgian ancestry as compared with normal controls. The difference in repeat number was more consistent if data of the two samples of patients was pooled. In this study a CAG trinucleotide repeat expansion was associated for the first time with a major psychiatric disorder. It is possible that the CAG trinucleotide repeat expansion is involved in the clinical expression of BPAD and that it is the molecular basis explaining the phenomenon of anticipation observed in this disorder.

  • 17.
    Lindström, Veronica
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Fagerqvist, Therese
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Eva, Nordström
    BioArctic Neuroscience AB.
    Eriksson, Fredrik
    BioArctic Neuroscience AB.
    Lord, Anna
    BioArctic Neuroscience AB.
    Tucker, Stina
    BioArctic Neuroscience AB.
    Anderssson, Jessica
    BioArctic Neuroscience AB.
    Johannesson, Malin
    BioArctic Neuroscience AB.
    Schell, Heinrich
    Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, Tübingen .
    Kahle, Philipp J
    Department of Neurodegeneration, Hertie Institute for Clinical Brain Research and German Center for Neurodegenerative Diseases, Tübingen .
    Möller, Christer
    BioArctic Neuroscience AB.
    Gellerfors, Pär
    Bergström, Joakim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Ingelsson, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Immunotherapy targeting α-synuclein protofibrils reduced pathology in (Thy-1)-h[A30P] α-synuclein mice2014Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 69, s. 134-143Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Several lines of evidence suggest that accumulation of aggregated alpha-synuclein (α-synuclein) in the central nervous system (CNS) is an early pathogenic event and therefore a suitable therapeutic target in Parkinson’s disease and other Lewy body disorders. In recent years, animal studies have indicated immunotherapy with antibodies directed against α-synuclein as a promising novel treatment strategy. Since large α-synuclein oligomers, or protofibrils, have been demonstrated to possess pronounced cytotoxic properties, such species should be particularly attractive as therapeutic targets. An α-synuclein protofibril-selective monoclonal antibody, mAb47, was evaluated in the (Thy-1)-h[A30P] α-synuclein transgenic mouse model, featuring an age- and motor dysfunction-associated increase of α-synuclein protofibrils in the CNS. As measured by ELISA, mAb47-treated mice displayed significantly lower levels of both soluble and membrane-associated protofibrils in the spinal cord. In addition, a trend for increased survival as a result of reduced motor symptoms was observed with antibody treatment. Taken together, this study demonstrates reduced levels of pathogenic α-synuclein and indicates a reduction of motor dysfunction in transgenic mice upon peripheral administration of an α-synuclein protofibril-selective antibody. Thus, immunotherapy with antibodies targeting toxic α-synuclein species holds promise as a future disease-modifying treatment in Parkinson’s disease and related disorders.

  • 18.
    Lord, Anna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Gumucio, Astrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Englund, Hillevi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sehlin, Dag
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Sundquist, Valentina Screpanti
    Söderberg, Linda
    Möller, Christer
    Gellerfors, Pär
    Lannfelt, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Pettersson, Frida Ekholm
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    Nilsson, Lars N G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för folkhälso- och vårdvetenskap, Geriatrik.
    An amyloid-beta protofibril-selective antibody prevents amyloid formation in a mouse model of Alzheimer's disease2009Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 36, nr 3, s. 425-434Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Human genetics link Alzheimer's disease pathogenesis to excessive accumulation of amyloid-beta (Abeta) in brain, but the symptoms do not correlate with senile plaque burden. Since soluble Abeta aggregates can cause synaptic dysfunctions and memory deficits, these species could contribute to neuronal dysfunction and dementia. Here we explored selective targeting of large soluble aggregates, Abeta protofibrils, as a new immunotherapeutic strategy. The highly protofibril-selective monoclonal antibody mAb158 inhibited in vitro fibril formation and protected cells from Abeta protofibril-induced toxicity. When the mAb158 antibody was administered for 4 months to plaque-bearing transgenic mice with both the Arctic and Swedish mutations (tg-ArcSwe), Abeta protofibril levels were lowered while measures of insoluble Abeta were unaffected. In contrast, when treatment began before the appearance of senile plaques, amyloid deposition was prevented and Abeta protofibril levels diminished. Therapeutic intervention with mAb158 was however not proven functionally beneficial, since place learning depended neither on treatment nor transgenicity. Our findings suggest that Abeta protofibrils can be selectively cleared with immunotherapy in an animal model that display highly insoluble Abeta deposits, similar to those of Alzheimer's disease brain.

  • 19. Namsolleck, P.
    et al.
    Boato, F.
    Schwengel, K.
    Paulis, L.
    Matho, K. S.
    Geurts, N.
    Thöne-Reineke, C.
    Lucht, K.
    Seidel, K.
    Hallberg, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi.
    Dahlöf, B.
    Unger, T.
    Hendrix, S.
    Steckelings, U. M.
    AT2-receptor stimulation enhances axonal plasticity after spinal cord injury by upregulating BDNF expression2013Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 51, nr SI, s. 177-191Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    It is widely accepted that the angiotensin AT2-receptor (AT2R) has neuroprotective features. In the present study we tested pharmacological AT2R-stimulation as a therapeutic approach in a model of spinal cord compression injury (SCI) in mice using the novel non-peptide AT2R-agonist, Compound 21 (C21). Complementary experiments in primary neurons and organotypic cultures served to identify underlying mechanisms. Functional recovery and plasticity of corticospinal tract (CST) fibers following SCI were monitored after application of C21 (0.3. mg/kg/day. i.p.) or vehicle for 4. weeks. Organotypic co-culture of GFP-positive entorhinal cortices with hippocampal target tissue served to evaluate the impact of C21 on reinnervation. Neuronal differentiation, apoptosis and expression of neurotrophins were investigated in primary murine astrocytes and neuronal cells.C21 significantly improved functional recovery after SCI compared to controls, and this significantly correlated with the increased number of CST fibers caudal to the lesion site. In vitro, C21 significantly promoted reinnervation in organotypic brain slice co-cultures (+50%) and neurite outgrowth of primary neurons (+25%). C21-induced neurite outgrowth was absent in neurons derived from AT2R-KO mice. In primary neurons, treatment with C21 further induced RNA expression of anti-apoptotic Bcl-2 (+75.7%), brain-derived neurotrophic factor (BDNF) (+53.7%), the neurotrophin receptors TrkA (+57.4%) and TrkB (+67.9%) and a marker for neurite growth, GAP43 (+103%), but not TrkC. Our data suggest that selective AT2R-stimulation improves functional recovery in experimental spinal cord injury through promotion of axonal plasticity and through neuroprotective and anti-apoptotic mechanisms. Thus, AT2R-stimulation may be considered for the development of a novel therapeutic approach for the treatment of spinal cord injury.

  • 20. Ruiz-Riquelme, A.
    et al.
    Sánchez-Iglesias, S.
    Rábano, A.
    Guillén-Navarro, E.
    Domingo-Jiménez, R.
    Ramos, A.
    Rosa, I.
    Senra, A.
    Nilsson, Peter
    KTH, Skolan för bioteknologi (BIO), Proteomik och nanobioteknologi. KTH, Centra, Science for Life Laboratory, SciLifeLab.
    García, Á.
    Araújo-Vilar, D.
    University of Santiago de Compostela-IDIS, Spain.
    Requena, J. R.
    University of Santiago de Compostela-IDIS, Spain.
    Larger aggregates of mutant seipin in Celia's Encephalopathy, a new protein misfolding neurodegenerative disease2015Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 83, s. 44-53, artikel-id 3572Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Celia's Encephalopathy (MIM #. 615924) is a recently discovered fatal neurodegenerative syndrome associated with a new BSCL2 mutation (c.985C>T) that results in an aberrant isoform of seipin (Celia seipin). This mutation is lethal in both homozygosity and compounded heterozygosity with a lipodystrophic BSCL2 mutation, resulting in a progressive encephalopathy with fatal outcomes at ages 6-8. Strikingly, heterozygous carriers are asymptomatic, conflicting with the gain of toxic function attributed to this mutation. Here we report new key insights about the molecular pathogenic mechanism of this new syndrome. Intranuclear inclusions containing mutant seipin were found in brain tissue from a homozygous patient suggesting a pathogenic mechanism similar to other neurodegenerative diseases featuring brain accumulation of aggregated, misfolded proteins. Sucrose gradient distribution showed that mutant seipin forms much larger aggregates as compared with wild type (wt) seipin, indicating an impaired oligomerization. On the other hand, the interaction between wt and Celia seipin confirmed by coimmunoprecipitation (CoIP) assays, together with the identification of mixed oligomers in sucrose gradient fractionation experiments can explain the lack of symptoms in heterozygous carriers. We propose that the increased aggregation and subsequent impaired oligomerization of Celia seipin leads to cell death. In heterozygous carriers, wt seipin might prevent the damage caused by mutant seipin through its sequestration into harmless mixed oligomers.

  • 21.
    Schuster, Jens
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Laan, Loora
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Klar, Joakim
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Jin, Zhe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Birnir: Molekylär fysiologi och neurovetenskap.
    Huss, Mikael
    Stockholm Univ, Dept Biochem & Biophys, Sci Life Lab, Wallenberg Long Term Bioinformat Support, Stockholm, Sweden.
    Korol, Sergiy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Birnir: Molekylär fysiologi och neurovetenskap.
    Noraddin, Feria Hikmet
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Sobol, Maria
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Birnir, Bryndis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Birnir: Molekylär fysiologi och neurovetenskap.
    Dahl, Niklas
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Transcriptomes of Dravet syndrome iPSC derived GABAergic cells reveal dysregulated pathways for chromatin remodeling and neurodevelopment2019Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 132, artikel-id 104583Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Dravet syndrome (DS) is an early onset refractory epilepsy typically caused by de novo heterozygous variants in SCN1A encoding the a-subunit of the neuronal sodium channel Na(v)1.1. The syndrome is characterized by age related progression of seizures, cognitive decline and movement disorders. We hypothesized that the distinct neurodevelopmental features in DS are caused by the disruption of molecular pathways in Na(v)1.1 haploinsufficient cells resulting in perturbed neural differentiation and maturation. Here, we established DS-patient and control induced pluripotent stem cell derived neural progenitor cells (iPSC NPC) and GABAergic interneuronal (iPSC GABA) cells. The DS-patient iPSC GABA cells showed a shift in sodium current activation and a perturbed response to induced oxidative stress. Transcriptome analysis revealed specific dysregulations of genes for chromatin structure, mitotic progression, neural plasticity and excitability in DS-patient iPSC NPCs and DS-patient iPSC GABA cells versus controls. The transcription factors FOXM1 and E2F1, positive regulators of the disrupted pathways for histone modification and cell cycle regulation, were markedly up-regulated in DS-iPSC GABA lines. Our study highlights transcriptional changes and disrupted pathways of chromatin remodeling in Na(v)1.1 haploinsufficient GABAergic cells, providing a molecular framework that overlaps with that of neurodevelopmental disorders and other epilepsies.

  • 22. Schuster, Jens
    et al.
    Laan, Loora
    Klar, Joakim
    Jin, Zhe
    Huss, Mikael
    Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. Stockholms universitet, Science for Life Laboratory (SciLifeLab).
    Korol, Sergiy
    Noraddin, Feria Hikmet
    Sobol, Maria
    Birnir, Bryndis
    Dahl, Niklas
    Transcriptomes of Dravet syndrome iPSC derived GABAergic cells reveal dysregulated pathways for chromatin remodeling and neurodevelopment2019Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 132, artikel-id 104583Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Dravet syndrome (DS) is an early onset refractory epilepsy typically caused by de novo heterozygous variants in SCN1A encoding the a-subunit of the neuronal sodium channel Na(v)1.1. The syndrome is characterized by age related progression of seizures, cognitive decline and movement disorders. We hypothesized that the distinct neurodevelopmental features in DS are caused by the disruption of molecular pathways in Na(v)1.1 haploinsufficient cells resulting in perturbed neural differentiation and maturation. Here, we established DS-patient and control induced pluripotent stem cell derived neural progenitor cells (iPSC NPC) and GABAergic interneuronal (iPSC GABA) cells. The DS-patient iPSC GABA cells showed a shift in sodium current activation and a perturbed response to induced oxidative stress. Transcriptome analysis revealed specific dysregulations of genes for chromatin structure, mitotic progression, neural plasticity and excitability in DS-patient iPSC NPCs and DS-patient iPSC GABA cells versus controls. The transcription factors FOXM1 and E2F1, positive regulators of the disrupted pathways for histone modification and cell cycle regulation, were markedly up-regulated in DS-iPSC GABA lines. Our study highlights transcriptional changes and disrupted pathways of chromatin remodeling in Na(v)1.1 haploinsufficient GABAergic cells, providing a molecular framework that overlaps with that of neurodevelopmental disorders and other epilepsies.

  • 23.
    Ström, Anna-Lena
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    Forsgren, Lars
    Umeå universitet, Medicinska fakulteten, Institutionen för farmakologi och klinisk neurovetenskap, Klinisk neurofysiologi.
    Holmberg, Monica
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Medicinsk och klinisk genetik.
    A role for both wild-type and expanded ataxin-7 in transcriptional regulation2005Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 20, nr 3, s. 646-655Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disease primarily affecting the brainstem, retina and Purkinje cells of the cerebellum. The disease is caused by a polyglutamine expansion in ataxin-7, a protein found in two complexes TFTC and STAGA, involved in transcriptional regulation. Transcriptional dysregulation has been implicated in the pathology of several polyglutamine diseases. In this paper, we analyzed the effect of both wild-type and expanded ataxin-7 on transcription driven by the co-activator CBP and the Purkinje cell expressed nuclear receptor RORα1. We could show that transcription mediated by both CBP and RORα1 was repressed by expanded ataxin-7. Interestingly, repression of transcription could also be observed with wild-type full-length ataxin-7, not only on CBP- and RORα1-mediated transcription, but also on basal transcription. The repression could be counteracted by inhibition of deacetylation, suggesting that ataxin-7 may act as a repressor of transcription by inhibiting the acetylation activity of TFTC and STAGA.

  • 24. Takenaga, Keizo
    et al.
    Nygren, Jim
    Zelenina, Marina
    Department of Woman and Child Health, Karolinska Institutet.
    Ohira, Miki
    Iuchi, Toshihiko
    Lukanidin, Eugen
    Sjöquist, Mats
    Kozlova, Elena N.
    Modified expression of Mts1/S100A4 protein in C6 glioma cells or surrounding astrocytes affects migration of tumor cells in vitro and in vivo2007Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 25, nr 3, s. 455-563Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The calcium-binding Mts1/S100A4 protein plays an important role in motility and metastatic activity of tumor cells. Recently we showed that Mts1/S100A4 is expressed in white matter astrocytes and influences their migration in vitro and in vivo. Here, we have investigated the role of Mts1/S100A4 expression in C6 glioma cells or surrounding astrocytes for migration of C6 cells on astrocytes, using short interference (si) RNA to silence Mts1/S100A4 expression. We find that in vitro, the migration of Mts1/S100A4 expressing and silenced C6 cells on astrocytes is predominantly dependent on the expression of Mts1/S100A4 in astrocytes, i.e. C6 cells preferably migrate on Mts1/S100A4-silenced astrocytes. In vivo, Mts1/S100A4-positive C6 cells preferably migrate in white matter. In contrast Mts1/S100A4-silenced C6 cells avoid white matter and migrate in gray matter and meninges. Thus, the migration pattern of C6 cells is affected by their intrinsic Mts1/S100A4 expression as well as Mts1/S100A4 expression in astrocytes. To investigate if Mts1/S100A4 has a significant role on brain tumor progression, we made quantitative RT-PCR analysis for the expression of S100A4/Mts1 in various grades of astrocytic tumors. Our data showed that high-grade glioblastomas express higher amount of S100A4/Mts1 than low-grade astrocytic tumors.

  • 25.
    Takenaga, Keizo
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Nygren, Jim
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Zelenina, Marina
    Ohira, Miki
    Iuchi, Toshihiko
    Lukanidin, Eugen
    Sjöquist, Mats
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Kozlova, Elena N.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Modified expression of Mts1/S100A4 protein in C6 glioma cells or surrounding astrocytes affects migration of tumor cells in vitro and in vivo2007Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 25, nr 3, s. 455-463Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The calcium-binding Mtsl/S100A4 protein plays an important role in motility and metastatic activity of tumor cells. Recently we showed that Mts1/S100A4 is expressed in white matter astrocytes and influences their migration in vitro and in vivo. Here, we have investigated the role of Mts1/S100A4 expression in C6 glioma cells or surrounding astrocytes for migration ofC6 cells on astrocytes, using short interference (si) RNA to silence Mtsl/S100A4 expression. We find that in vitro, the migration of Mts1/S100A4 expressing and silenced C6 cells on astrocytes is predominantly dependent on the expression of Mts1/S100A4 in astrocytes, i.e. C6 cells preferably migrate on Mts1/S100A4-silenced astrocytes. In vivo, Mtsl/S100A4-positive C6 cells preferably migrate in white matter. In contrast Mts1/S100A4-silenced C6 cells avoid white matter and migrate in gray matter and meninges. Thus, the migration pattern ofC6 cells is affected by their intrinsic Mtsl/S100A4 expression as well as Mtsl/S100A4 expression in astrocytes. To investigate if Mts1/S100A4 has a significant role on brain tumor progression, we made quantitative RT-PCR analysis for the expression of S100A4/Mtsl in various grades of astrocytic tumors. Our data showed that high-grade glioblastomas express higher amount of S100A4/Mtsl than low-grade astrocytic tumors.

  • 26.
    Tingaud-Sequeira, Angèle
    et al.
    Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France.
    Raldúa, Demetrio
    IDÆA-CSIC, Barcelona, Spain.
    Lavie, Julie
    Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France.
    Mathieu, Guilaine
    Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France.
    Bordier, Magali
    Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France; Service de Génétique Médicale, Centre hospitalier universitaire (CHU) Bordeaux, Hôpital Pellegrin, Bordeaux, France.
    Knoll-Gellida, Anja
    Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France.
    Rambeau, Pierre
    Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France.
    Coupry, Isabelle
    Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France.
    André, Michèle
    Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France.
    Malm, Eva
    Department of Ophthalmology, Lund University Hospital, Lund, Sweden.
    Möller, Claes
    Örebro universitet, Institutionen för hälsovetenskaper. Region Örebro län.
    Andreasson, Sten
    Department of Ophthalmology, Lund University Hospital, Lund, Sweden.
    Rendtorff, Nanna
    Department Audiology, Region Huvudstaden, Copenhagen, Denmark; Department of Clinical Genetics, The Kennedy Center, Rigshospitalet, Copenhagen, Denmark; Department Audiology, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine Copenhagen, University of Copenhagen, Copenhagen, Denmark.
    Tranebjaerg, Lisbeth
    Department Audiology, Region Huvudstaden, Copenhagen, Denmark; Department of Clinical Genetics, The Kennedy Center, Rigshospitalet, Copenhagen, Denmark; Department Audiology, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine Copenhagen, University of Copenhagen, Copenhagen, Denmark.
    Koenig, Michel
    Laboratoire de Génétique Moléculaire et unité, INSERM UMR_S827, University Medical Centre of Montpellier (IURC), Montpellier, France.
    Lacombe, Didier
    Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France; Service de Génétique Médicale, Centre hospitalier universitaire (CHU) Bordeaux, Hôpital Pellegrin, Bordeaux, France.
    Goizet, Cyril
    Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France; Service de Génétique Médicale, Centre hospitalier universitaire (CHU) Bordeaux, Hôpital Pellegrin, Bordeaux, France.
    Babin, Patrick
    Maladies Rares: Génétique et Métabolisme (MRGM), INSERM U1211, Univ. Bordeaux, Bordeaux, France.
    Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC2017Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 98, s. 36-51Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    ABHD12 mutations have been linked to neurodegenerative PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and early-onset cataract), a rare, progressive, autosomal, recessive disease. Although ABHD12 is suspected to play a role in the lysophosphatidylserine and/or endocannabinoid pathways, its precise functional role(s) leading to PHARC disease had not previously been characterized. Cell and zebrafish models were designed to demonstrate the causal link between an identified new missense mutation p.T253R, characterized in ABHD12 from a young patient, the previously characterized p.T202I and p.R352* mutations, and the associated PHARC. Measuring ABHD12 monoacylglycerol lipase activity in transfected HEK293 cells demonstrated inhibition with mutated isoforms. Both the expression pattern of zebrafish abhd12 and the phenotype of specific antisense morpholino oligonucleotide gene knockdown morphants were consistent with human PHARC hallmarks. High abhd12 transcript levels were found in the optic tectum and tract, colocalized with myelin basic protein, and in the spinal cord. Morphants have myelination defects and concomitant functional deficits, characterized by progressive ataxia and motor skill impairment. A disruption of retina architecture and retinotectal projections was observed, together with an inhibition of lens clarification and a low number of mechanosensory hair cells in the inner ear and lateral line system. The severe phenotypes in abhd12 knockdown morphants were rescued by introducing wild-type human ABHD12 mRNA, but not by mutation-harboring mRNAs. Zebrafish may provide a suitable vertebrate model for ABHD12 insufficiency and the study of functional impairment and potential therapeutic rescue of this rare, neurodegenerative disease.

  • 27.
    Tokuda, Eiichi
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Okawa, Eriko
    Watanabe, Shunsuke
    Ono, Shin-ichi
    Marklund, Stefan
    Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap, Klinisk kemi.
    Dysregulation of intracellular copper homeostasis is common to transgenic mice expressing human mutant superoxide dismutase-1s regardless of their copper-binding abilities2013Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 54, s. 308-319Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Over 170 mutations in superoxide dismutase-1 (SOD1) have been linked to amyotrophic lateral sclerosis (ALS). The properties of SOD1 mutants differ considerably including copper-binding abilities. Nevertheless, they cause the same disease phenotype, suggesting a common neurotoxic pathway. We have previously reported that copper homeostasis is disturbed in spinal cords of SOD1(G93A) mice. However, it is unknown whether copper dyshomeostasis is induced by other SOD1 mutants. Using the additional mouse strains SOD1(G127insTGGG), SOD1(G85R), and SOD1(D90A), which express SOD1 mutants with different copper-binding abilities, we show that copper dyshomeostasis is common to SOD1 mutants. The SOD1 mutants shifted the copper trafficking systems toward copper accumulation in spinal cords of the mice. Copper contents bound to the SOD1 active site varied considerably between SOD1 mutants. Still, copper bound to other ligands in the spinal cord were markedly increased in all. Zinc was also increased, whereas there were no changes in magnesium, calcium, aluminum, manganese and iron. Further support for a role of copper dyshomeostasis in ALS was gained from results of pharmacological intervention. Ammonium tetrathiomolybdate (TTM), a copper chelating agent, prolonged survival and slowed the disease progression of SOD1(G93A) mice, even when the treatment was started after the disease onset. TTM markedly attenuated pathology, including the loss of motor neurons and axons, and atrophy of skeletal muscles. Additionally, TTM decreased amounts of SOD1 aggregates. We propose that pharmacological agents that are capable of modulating copper dyshomeostasis, such as TTM, might be beneficial for the treatment of ALS caused by SOD1 mutations.

  • 28. Vannini, Patrizia
    et al.
    Lehmann, Christoph
    Dierks, Thomas
    Jann, Kay
    Viitanen, Matti
    Wahlund, Lars-Olof
    Almkvist, Ove
    Stockholms universitet, Samhällsvetenskapliga fakulteten, Psykologiska institutionen.
    Failure to modulate neural response to increased task demand in mild Alzheimer's disease: fMRI study of visuospatial processing2008Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 31, nr 3, s. 287-297Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Alzheimer's disease (AD) is characterized by disturbances of visuospatial cognition. Given that these impairments are closely related to metabolic and neuropathological changes, our study aimed to investigate the functional competency of brain regions in the visuospatial networks responsible for early clinical symptoms in AD using event-related functional magnetic resonance imaging (fMRI). Participants (13AD patients with mild symptoms and 13 age- and education-matched controls) performed an angle discrimination task with varying task demand. Using a novel approach that modeled the dependency of the blood oxygenation level-dependent (BOLD) signal on the subject's reaction time allowed us to investigate task demand-dependent signal changes between the groups. Both groups demonstrated overlapping neural networks engaged in angle discrimination, including the parieto-occipital and frontal regions. In several network regions, AD patients showed a significantly weaker and sometimes no BOLD signal due to increased task demand compared with controls, demonstrating failure to modulate the neural response to increased task demand. A general task demand-independent increase of activation in AD patients compared with controls was found in right middle temporal gyrus. This latter finding may indicate an attempt to compensate for dysfunctional areas in the dorsal visual pathway. These results confirm deficits in visuospatial abilities, which occur early in AD, and offer new insights into the neural mechanisms underlying this impairment.

  • 29.
    Wootz, Hanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Enjin, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Wallen-Mackenzie, Åsa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Lindholm, Dan
    Kullander, Klas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Genetisk utvecklingsbiologi.
    Reduced VGLUT2 expression increases motor neuron viability in Sod1(G93A) mice2010Ingår i: Neurobiology of Disease, ISSN 0969-9961, E-ISSN 1095-953X, Vol. 37, nr 1, s. 58-66Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Glutamate-induced excitotoxicity has been suggested to influence pathogenesis in amyotrophic lateral sclerosis (ALS). Vesicular glutamate transporters (VGLUTs) are responsible for transport of glutamate into synaptic vesicles. Nerve terminals that envelop motor neurons in the spinal cord contain VGLUT2 and are likely responsible for most glutamate release on motor neurons. The role of VGLUT2 in ALS and its potential role to influence motor neuron survival have not previously been studied. Here, in a mouse model of ALS. we show that genetic reduction of VGLUT2 protein levels rescues motor neurons in the lumbar spinal cord and in the brainstem as well as neuromuscular junctions in tibialis anterior. Although the number of remaining motor neurons increased. neither disease onset nor life span was affected. We also show that the motor neuron subpopulation-specific markers calcitonin/calcitonin-related polypeptide alpha (Calca) and estrogen related receptor beta (ERR beta) respond in a similar way to reduced VGLUT2 as the whole motor neuron population suggesting that the rescued motor neurons are not of a particular motor unit type. Taken together, this suggests that reduced levels of VGLUT2 decrease motor neuron degeneration but do not prevent loss of motor neuron function in the SOD1(G93A) mouse model for ALS. (C) 2009 Elsevier Inc. All rights reserved

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