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The Mitochondrial Peptidasome, PreP, relation to Alzheimer Disease
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik. (Prof. Elzbieta Glaser)
2009 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

Amyloid-β (Aβ) is the toxic peptide implicated in the pathogenesis of Alzheimer Disease (AD). Accumulation of Aβ has been shown in brain mitochondria from AD patients and AD mice models. The occurrence of Aβ in the mitochondrial matrix leads to free radical generation and apoptosis in neurons.

In our studies, Aβ was found in brain mitochondria of living patients with plaque pathology. Extracellular Aβ was taken up by neuroblastoma cells and was found in the mitochondria. Moreover, we showed that Aβ40 and Aβ42 are transported into mitochondria via the Translocase of the Outer Membrane, the TOM machinery.

We have identified the mitochondrial Aβ-degrading protease hPreP, in human brain mitochondrial matrix. PreP is a metalloprotease, originally identified as presequence protease, but was also shown to degrade other unstructured peptides including Aβ. Immunoinactivation of PreP in human brain mitochondria revealed PreP to be the protease responsible for Aβ degradation in mitochondria.

Also, we have investigated if genetic variation in the gene encoding hPreP is associated with AD by genotyping 19 single nucleotide polymorphisms (SNPs) in the Swedish population. The study did not show a genetic association between any of the genotyped SNPs and the risk to AD. However, the biochemical analysis of four SNPs selected on the basis of their location within a structural homology model of hPreP revealed a decreased activity compared to wildtype.

Interestingly, the activity of PreP in human brain mitochondrial matrix in AD individuals was significantly lower compared to non-dement aged-matched controls. These findings were also confirmed in brain mitochondrial matrix of AD mouse models. These results suggest that a decreased PreP activity may contribute to Aβ aggregation and accumulation inside mitochondria leading to neuronal death in AD. In summary, our findings show that the degradation of Aβ by hPreP may be of importance in the pathology of AD.

sted, utgiver, år, opplag, sider
Stockholm: Department of Biochemistry and Biophysics, Stockholm University , 2009. , s. 64
HSV kategori
Forskningsprogram
biokemi
Identifikatorer
URN: urn:nbn:se:su:diva-29044ISBN: 978-91-7155-918-0 (tryckt)OAI: oai:DiVA.org:su-29044DiVA, id: diva2:231469
Disputas
2009-09-25, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00 (engelsk)
Opponent
Veileder
Merknad

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Submitted. Paper 4: In progress.

Tilgjengelig fra: 2009-09-03 Laget: 2009-08-07 Sist oppdatert: 2017-02-22bibliografisk kontrollert
Delarbeid
1. The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae
Åpne denne publikasjonen i ny fane eller vindu >>The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae
Vise andre…
2008 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 105, nr 35, s. 13145-13150Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The amyloid beta-peptide (Abeta) has been suggested to exert its toxicity intracellularly. Mitochondrial functions can be negatively affected by Abeta and accumulation of Abeta has been detected in mitochondria. Because Abeta is not likely to be produced locally in mitochondria, we decided to investigate the mechanisms for mitochondrial Abeta uptake. Our results from rat mitochondria show that Abeta is transported into mitochondria via the translocase of the outer membrane (TOM) machinery. The import was insensitive to valinomycin, indicating that it is independent of the mitochondrial membrane potential. Subfractionation studies following the import experiments revealed Abeta association with the inner membrane fraction, and immunoelectron microscopy after import showed localization of Abeta to mitochondrial cristae. A similar distribution pattern of Abeta in mitochondria was shown by immunoelectron microscopy in human cortical brain biopsies obtained from living subjects with normal pressure hydrocephalus. Thus, we present a unique import mechanism for Abeta in mitochondria and demonstrate both in vitro and in vivo that Abeta is located to the mitochondrial cristae. Importantly, we also show that extracellulary applied Abeta can be internalized by human neuroblastoma cells and can colocalize with mitochondrial markers. Together, these results provide further insight into the mitochondrial uptake of Abeta, a peptide considered to be of major significance in Alzheimer's disease.

Emneord
Alzheimer disease, protein import, human brain biopsies
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-14872 (URN)10.1073/pnas.0806192105 (DOI)000259343000093 ()18757748 (PubMedID)
Tilgjengelig fra: 2009-01-26 Laget: 2009-01-26 Sist oppdatert: 2017-12-13bibliografisk kontrollert
2. Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP
Åpne denne publikasjonen i ny fane eller vindu >>Degradation of the amyloid beta-protein by the novel mitochondrial peptidasome, PreP
Vise andre…
2006 (engelsk)Inngår i: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 281, nr 39, s. 29096-29104Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Recently we have identified the novel mitochondrial peptidase responsible for degrading presequences and other short unstructured peptides in mitochondria, the presequence peptidase, which we named PreP peptidasome. In the present study we have identified and characterized the human PreP homologue, hPreP, in brain mitochondria, and we show its capacity to degrade the amyloid beta-protein (Abeta). PreP belongs to the pitrilysin oligopeptidase family M16C containing an inverted zinc-binding motif. We show that hPreP is localized to the mitochondrial matrix. In situ immuno-inactivation studies in human brain mitochondria using anti-hPreP antibodies showed complete inhibition of proteolytic activity against Abeta. We have cloned, overexpressed, and purified recombinant hPreP and its mutant with catalytic base Glu(78) in the inverted zinc-binding motif replaced by Gln. In vitro studies using recombinant hPreP and liquid chromatography nanospray tandem mass spectrometry revealed novel cleavage specificities against Abeta-(1-42), Abeta-(1-40), and Abeta Arctic, a protein that causes increased protofibril formation an early onset familial variant of Alzheimer disease. In contrast to insulin degrading enzyme, which is a functional analogue of hPreP, hPreP does not degrade insulin but does degrade insulin B-chain. Molecular modeling of hPreP based on the crystal structure at 2.1 A resolution of AtPreP allowed us to identify Cys(90) and Cys(527) that form disulfide bridges under oxidized conditions and might be involved in redox regulation of the enzyme. Degradation of the mitochondrial Abeta by hPreP may potentially be of importance in the pathology of Alzheimer disease.

HSV kategori
Identifikatorer
urn:nbn:se:su:diva-8748 (URN)10.1074/jbc.M602532200 (DOI)16849325 (PubMedID)
Tilgjengelig fra: 2007-12-21 Laget: 2007-12-21 Sist oppdatert: 2017-12-13bibliografisk kontrollert
3. Genetic and biochemical studies of SNPs in the mitochondrial Aβ-degrading protease, hPreP
Åpne denne publikasjonen i ny fane eller vindu >>Genetic and biochemical studies of SNPs in the mitochondrial Aβ-degrading protease, hPreP
Vise andre…
(engelsk)Manuskript (Annet vitenskapelig)
HSV kategori
Forskningsprogram
biokemi
Identifikatorer
urn:nbn:se:su:diva-29250 (URN)
Tilgjengelig fra: 2009-08-18 Laget: 2009-08-18 Sist oppdatert: 2017-02-22bibliografisk kontrollert
4. Decreased proteolytic activity of the PreP peptidasome in Alzheimer disease brain mitochondria and transgenic models
Åpne denne publikasjonen i ny fane eller vindu >>Decreased proteolytic activity of the PreP peptidasome in Alzheimer disease brain mitochondria and transgenic models
Vise andre…
(engelsk)Manuskript (Annet vitenskapelig)
HSV kategori
Identifikatorer
urn:nbn:se:su:diva-29251 (URN)
Tilgjengelig fra: 2009-08-18 Laget: 2009-08-18 Sist oppdatert: 2017-02-22bibliografisk kontrollert

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