Proximity proteomics reveals unique and shared pathological features between multiple system atrophy and Parkinson's disease.

IF 6.2 2区 医学 Q1 NEUROSCIENCES
Solji G Choi, Tyler R Tittle, Raj R Barot, Dakota J Betts, Johnie J Gallagher, Jeffrey H Kordower, Yaping Chu, Bryan A Killinger
{"title":"Proximity proteomics reveals unique and shared pathological features between multiple system atrophy and Parkinson's disease.","authors":"Solji G Choi, Tyler R Tittle, Raj R Barot, Dakota J Betts, Johnie J Gallagher, Jeffrey H Kordower, Yaping Chu, Bryan A Killinger","doi":"10.1186/s40478-025-01958-5","DOIUrl":null,"url":null,"abstract":"<p><p>Synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are neurodegenerative diseases with shared clinical and pathological features. Aggregates of alpha-synuclein (αsyn) phosphorylated at serine 129 (PSER129) are hallmarks of synucleinopathies, which, for PD/DLB, are found predominantly in neurons, whereas in MSA, aggregates are primarily found in oligodendroglia. It remains unclear whether the distinct pathological presentations of PD/DLB and MSA are manifestations of unique or shared pathological processes. Using the in-situ proximity labeling technique of biotinylation by antibody recognition (BAR), we compared aggregated αsyn-interactomes (BAR-PSER129) and total αsyn-interactomes (BAR-MJFR1) between MSA (n = 5) and PD/DLB (n = 10) in forebrain and midbrain structures. Comparison between MSA and PD/DLB-enriched proteins revealed 79 PD/DLB-differentially abundant proteins and only three MSA-differentially abundant proteins (CBR1, CRYAB, and GFAP). Pathway enrichment analysis revealed that vesicle/SNARE-associated pathways dominated PD/DLB interactions, whereas MSA was strongly enriched for metabolic/catabolic, iron, and cellular oxidant detoxification pathways. A subnetwork of cytosolic antioxidant enzymes called peroxiredoxins drove cellular detoxification pathway enrichment in MSA. A network of 26 proteins, including neuronal-specific proteins (e.g., SYNGR3) with HSPA8 at the core, was shared between MSA and DLB/PD. Extracellular exosome pathways were universally enriched regardless of the disease or BAR target protein. In conclusion, synucleinopathies have divergent and convergent αsyn-aggregate interactions, indicating unique and shared pathogenic mechanisms. MSA uniquely involves oxidant detoxification processes in glial cells, while vesicular processes in neurons dominate PD/DLB. Shared interactions, specifically SYNGR3, between MSA and PD/DLB suggest that neuronal axons are the origin of both diseases. In conclusion, we provide αsyn protein interaction maps for two distinct synucleinopathies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"65"},"PeriodicalIF":6.2000,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11931798/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Acta Neuropathologica Communications","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1186/s40478-025-01958-5","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

Synucleinopathies such as Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA) are neurodegenerative diseases with shared clinical and pathological features. Aggregates of alpha-synuclein (αsyn) phosphorylated at serine 129 (PSER129) are hallmarks of synucleinopathies, which, for PD/DLB, are found predominantly in neurons, whereas in MSA, aggregates are primarily found in oligodendroglia. It remains unclear whether the distinct pathological presentations of PD/DLB and MSA are manifestations of unique or shared pathological processes. Using the in-situ proximity labeling technique of biotinylation by antibody recognition (BAR), we compared aggregated αsyn-interactomes (BAR-PSER129) and total αsyn-interactomes (BAR-MJFR1) between MSA (n = 5) and PD/DLB (n = 10) in forebrain and midbrain structures. Comparison between MSA and PD/DLB-enriched proteins revealed 79 PD/DLB-differentially abundant proteins and only three MSA-differentially abundant proteins (CBR1, CRYAB, and GFAP). Pathway enrichment analysis revealed that vesicle/SNARE-associated pathways dominated PD/DLB interactions, whereas MSA was strongly enriched for metabolic/catabolic, iron, and cellular oxidant detoxification pathways. A subnetwork of cytosolic antioxidant enzymes called peroxiredoxins drove cellular detoxification pathway enrichment in MSA. A network of 26 proteins, including neuronal-specific proteins (e.g., SYNGR3) with HSPA8 at the core, was shared between MSA and DLB/PD. Extracellular exosome pathways were universally enriched regardless of the disease or BAR target protein. In conclusion, synucleinopathies have divergent and convergent αsyn-aggregate interactions, indicating unique and shared pathogenic mechanisms. MSA uniquely involves oxidant detoxification processes in glial cells, while vesicular processes in neurons dominate PD/DLB. Shared interactions, specifically SYNGR3, between MSA and PD/DLB suggest that neuronal axons are the origin of both diseases. In conclusion, we provide αsyn protein interaction maps for two distinct synucleinopathies.

求助全文
约1分钟内获得全文 求助全文
来源期刊
Acta Neuropathologica Communications
Acta Neuropathologica Communications Medicine-Pathology and Forensic Medicine
CiteScore
11.20
自引率
2.80%
发文量
162
审稿时长
8 weeks
期刊介绍: "Acta Neuropathologica Communications (ANC)" is a peer-reviewed journal that specializes in the rapid publication of research articles focused on the mechanisms underlying neurological diseases. The journal emphasizes the use of molecular, cellular, and morphological techniques applied to experimental or human tissues to investigate the pathogenesis of neurological disorders. ANC is committed to a fast-track publication process, aiming to publish accepted manuscripts within two months of submission. This expedited timeline is designed to ensure that the latest findings in neuroscience and pathology are disseminated quickly to the scientific community, fostering rapid advancements in the field of neurology and neuroscience. The journal's focus on cutting-edge research and its swift publication schedule make it a valuable resource for researchers, clinicians, and other professionals interested in the study and treatment of neurological conditions.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信