دورية أكاديمية
Leveraging the preformed fibril model to distinguish between alpha-synuclein inclusion- and nigrostriatal degeneration-associated immunogenicity.
العنوان: | Leveraging the preformed fibril model to distinguish between alpha-synuclein inclusion- and nigrostriatal degeneration-associated immunogenicity. |
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المؤلفون: | Stoll AC; Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA; Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI, USA., Sortwell CE; Department of Translational Neuroscience, Michigan State University, Grand Rapids, MI, USA. Electronic address: sortwell@msu.edu. |
المصدر: | Neurobiology of disease [Neurobiol Dis] 2022 Sep; Vol. 171, pp. 105804. Date of Electronic Publication: 2022 Jun 25. |
نوع المنشور: | Journal Article; Review; Research Support, N.I.H., Extramural |
اللغة: | English |
بيانات الدورية: | Publisher: Academic Press Country of Publication: United States NLM ID: 9500169 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1095-953X (Electronic) Linking ISSN: 09699961 NLM ISO Abbreviation: Neurobiol Dis Subsets: MEDLINE |
أسماء مطبوعة: | Publication: San Diego, CA : Academic Press Original Publication: Oxford : Blackwell Science, c1994- |
مواضيع طبية MeSH: | Parkinson Disease*/pathology , alpha-Synuclein*/metabolism, Humans ; Inflammation/pathology ; Lewy Bodies/metabolism ; Substantia Nigra/metabolism |
مستخلص: | Neuroinflammation has become a well-accepted pathologic hallmark of Parkinson's disease (PD). However, it remains unclear whether inflammation, triggered by α-syn aggregation and/or degeneration, contributes to the progression of the disease. Studies examining neuroinflammation in PD are unable to distinguish between Lewy body-associated inflammation and degeneration-associated inflammation, as both pathologies are present simultaneously. Intrastriatal and intranigral injections of alpha-synuclein (α-syn) preformed fibrils (PFFs) results in two distinct pathologic phases: Phase 1: The accumulation and peak formation of α-syn inclusions in nigrostriatal system and, Phase 2: Protracted dopaminergic neuron degeneration. In this review we summarize the current understanding of neuroinflammation in the α-syn PFF model, leveraging the distinct Phase 1 aggregation phase and Phase 2 degeneration phase to guide our interpretations. Studies consistently demonstrate an association between pathologic α-syn aggregation in the substantia nigra (SN) and activation of the innate immune system. Further, major histocompatibility complex-II (MHC-II) antigen presentation is proportionate to inclusion load. The α-syn aggregation phase is also associated with peripheral and adaptive immune cell infiltration to the SN. These findings suggest that α-syn like aggregates are immunogenic and thus have the potential to contribute to the degenerative process. Studies examining neuroinflammation during the neurodegenerative phase reveal elevated innate, adaptive, and peripheral immune cell markers, however limitations of single time point experimental design hinder interpretations as to whether this neuroinflammation preceded, or was triggered by, nigral degeneration. Longitudinal studies across both the aggregation and degeneration phases of the model suggest that microglial activation (MHC-II) is greater in magnitude during the aggregation phase that precedes degeneration. Overall, the consistency between neuroinflammatory markers in the parkinsonian brain and in the α-syn PFF model, combined with the distinct aggregation and degenerative phases, establishes the utility of this model platform to yield insights into pathologic events that contribute to neuroinflammation and disease progression in PD. (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) |
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معلومات مُعتمدة: | R21 NS099416 United States NS NINDS NIH HHS; R21 NS111333 United States NS NINDS NIH HHS; R33 NS099416 United States NS NINDS NIH HHS; T32 GM092715 United States GM NIGMS NIH HHS |
فهرسة مساهمة: | Keywords: Aggregation; Astrocytes; Inclusions; Microglia; Neuroinflammation; Parkinson's disease; Synucleinopathy |
المشرفين على المادة: | 0 (alpha-Synuclein) |
تواريخ الأحداث: | Date Created: 20220628 Date Completed: 20220726 Latest Revision: 20240607 |
رمز التحديث: | 20240607 |
مُعرف محوري في PubMed: | PMC9803935 |
DOI: | 10.1016/j.nbd.2022.105804 |
PMID: | 35764290 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1095-953X |
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DOI: | 10.1016/j.nbd.2022.105804 |