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Alpha-Synuclein Reactive Antibodies as Diagnostic Biomarkers in Blood Sera of Parkinson's Disease Patients
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics. (Morozova-Roche)
Institute of Normal Physiology, Moscow.
Institute of Biochemistry, Vilnius .
Institute of Biochemistry, Vilnius .
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2011 (English)In: PLoS One, ISSN 1932-6203, Vol. 6, no 4, e18513- p.Article in journal (Refereed) Published
Abstract [en]

Background

Auto-antibodies with specificity to self-antigens have been implicated in a wide variety of neurological diseases, including Parkinson's (PD) and Alzheimer's diseases, being sensitive indicators of neurodegeneration and focus for disease prevention. Of particular interest are the studies focused on the auto-immune responses to amyloidogenic proteins associated with diseases and their applications in therapeutic treatments such as vaccination with amyloid antigens and antibodies in PD, Alzheimer's disease and potentially other neurodegeneration ailments.

Methodology/Principal Findings

Generated auto-antibodies towards the major amyloidogenic protein involved in PD Lewy bodies – α-synuclein and its amyloid oligomers and fibrils were measured in the blood sera of early and late PD patients and controls by using ELISA, Western blot and Biacore surface plasmon resonance. We found significantly higher antibody levels towards monomeric α-synuclein in the blood sera of PD patients compared to controls, though the responses decreased with PD progression (P<0.0001). This indicates potential protective role of autoimmunity in maintaining the body homeostasis and clearing protein species whose disbalance may lead to amyloid assembly. There were no noticeable immune responses towards amyloid oligomers, but substantially increased levels of IgGs towards α-synuclein amyloid fibrils both in PD patients and controls, which subsided with the disease progression (P<0.0001). Pooled IgGs from PD patients and controls interacted also with the amyloid fibrils of Aβ (1–40) and hen lysozyme, however the latter were recognized with lower affinity. This suggests that IgGs bind to the generic amyloid conformational epitope, displaying higher specificity towards human amyloid species associated with neurodegeneration.

Conclusions/Significance

Our findings may suggest the protective role of autoimmunity in PD and therefore immune reactions towards PD major amyloid protein – α-synuclein can be of value in the development of treatment and diagnostic strategies, especially during the early disease stages.

Place, publisher, year, edition, pages
Public Library of Science , 2011. Vol. 6, no 4, e18513- p.
Keyword [en]
amyloid, biomarker, Parkinson's disease
National Category
Biological Sciences
Research subject
Biochemistry
Identifiers
URN: urn:nbn:se:umu:diva-43962DOI: 10.1371/journal.pone.0018513OAI: oai:DiVA.org:umu-43962DiVA: diva2:417360
Projects
amyloid research
Available from: 2011-05-16 Created: 2011-05-16 Last updated: 2012-08-15Bibliographically approved
In thesis
1. Studies of in vivo prostate amyloidosis and autoimmune responses towards amyloid structures in neurodegeneration
Open this publication in new window or tab >>Studies of in vivo prostate amyloidosis and autoimmune responses towards amyloid structures in neurodegeneration
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Studier av in vivo prostata amyloidos och autoimmunitet mot amyloida strukturer vid neurodegenerativa sjukdomar
Abstract [en]

By using multidisciplinary analysis of CA inclusions in prostate glands of patients diagnosed with prostate cancer, we have revealed that their major components are the amyloid forms of S100A8 and S100A9 proteins associated with numerous inflammatory conditions and types of cancer. We have demonstrated that material closely resembling CA can be produced from S100A8/A9 in vitro and shows the characters of amyloids. This process is facilitated by calcium or zinc, both of which are abundant in ex vivo inclusions. These observations were supported by computational analysis of the S100A8/A9 calcium-dependent aggregation propensity profiles. We have found DNA and proteins from Escherichia coli in CA bodies, suggesting that their formation is likely to be associated with bacterial infection. CA inclusions were also accompanied by the activation of macrophages and by an increase in the concentration of S100A8/A9 in the surrounding tissues, indicating inflammatory reactions. These findings, taken together, suggest a link between bacterial infection, inflammation and amyloid deposition of pro-inflammatory proteins S100A8/A9 in the prostate gland, such that a self-perpetuating cycle can be triggered and may increase the risk of malignancy in the ageing prostate.

We evaluated the autoimmune reactions to endocrine (insulin) and astrocytical (S100B) biomarkers in the blood sera of PD patients compared with healthy controls. Peripheral immune responses can be sensitive indicators of disease pathology. We found a statistically significant increase of the autoimmune responses to both antigens in patients compared with controls. Heterogeneity of the immune responses observed in patients may reflect the modulating effect of multiple variables associated with neurodegeneration and also changes in the basic mechanisms of individual autoimmune reactivity. We did not detect any pronounced immune reactions towards insulin amyloid fibrils and oligomers in patients, indicating that an amyloid-specific conformational epitope is not involved in immune recognition of this amyloid type. Immune reactions towards S100B and insulin may reflect the neurodegenerative brain damaging processes and impaired insulin homeostasis occurring in PD.

Generated auto-antibodies towards the major amyloidogenic protein involved in PD Lewy bodies - a-synuclein and its amyloid oligomers and fibrils were measured in the blood sera of early and late PD patients and controls by using ELISA, Western blot and Biacore surface plasmon resonance analyses. We found significantly higher antibody levels towards monomeric a-synuclein in the blood sera of PD patients compared to controls, though the responses decreased with PD progression. There were no noticeable immune responses towards amyloid oligomers, but substantially increased levels of IgGs towards a-synuclein amyloid fibrils both in PD patients and controls, which subsided with the disease progression. Pooled IgGs from PD patients and controls interacted also with amyloid fibrils of Ab (1-40) and hen lysozyme, however the latter were recognized with lower affinity. This suggests that IgGs bind to amyloid conformational epitope, though displaying higher specificity towards human amyloid species associated with neurodegeneration. The findings suggest the protective role of autoimmunity in PD and therefore immune reactions towards PD major amyloid protein - a-synuclein can be used in treatment strategies and in diagnostics, especially in identifying early disease.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2010. 40 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1386
Keyword
amyloid, amyloidosis, immune reactivity, S100A8/A9, insulin, α-synuclein
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medical Biochemistry
Identifiers
urn:nbn:se:umu:diva-37561 (URN)978-91-7459-110-1 (ISBN)
Public defence
2010-12-01, KB3A9, Umeå University, Umeå, KBC building, 09:00 (English)
Opponent
Supervisors
Available from: 2010-11-12 Created: 2010-11-09 Last updated: 2012-08-15Bibliographically approved

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Yanamandra, KiranForsgren, LarsMorozova-Roche, Ludmilla
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