Choi Solji G, Tittle Tyler R, Barot Raj R, Betts Dakota J, Gallagher Johnie J, Kordower Jeffrey H, Chu Yaping, Killinger Bryan A
Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.
University of Illinois at Chicago, College of Medicine, Chicago, IL, USA.
Acta Neuropathol Commun. 2025 Mar 23;13(1):65. doi: 10.1186/s40478-025-01958-5.
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.
诸如帕金森病（PD）、路易体痴呆（DLB）和多系统萎缩（MSA）等突触核蛋白病是具有共同临床和病理特征的神经退行性疾病。在丝氨酸129位点磷酸化的α-突触核蛋白（αsyn）聚集体（PSER129）是突触核蛋白病的标志，对于PD/DLB而言，主要在神经元中发现，而在MSA中，聚集体主要在少突胶质细胞中发现。目前尚不清楚PD/DLB和MSA不同的病理表现是独特病理过程还是共享病理过程的表现。利用抗体识别生物素化的原位邻近标记技术（BAR），我们比较了MSA（n = 5）和PD/DLB（n = 10）在前脑和中脑结构中的聚集αsyn相互作用组（BAR-PSER129）和总αsyn相互作用组（BAR-MJFR1）。MSA和富含PD/DLB的蛋白质之间的比较揭示了79种PD/DLB差异丰富的蛋白质和仅三种MSA差异丰富的蛋白质（CBR1、CRYAB和GFAP）。通路富集分析表明，囊泡/SNARE相关通路在PD/DLB相互作用中占主导地位，而MSA在代谢/分解代谢、铁和细胞氧化解毒通路中强烈富集。一个称为过氧化物酶的胞质抗氧化酶子网推动了MSA中细胞解毒通路的富集。包括以HSPA8为核心的神经元特异性蛋白质（如SYNGR3）在内的26种蛋白质网络在MSA和DLB/PD之间共享。无论疾病或BAR靶蛋白如何，细胞外外泌体通路普遍富集。总之，突触核蛋白病具有不同和趋同的αsyn聚集体相互作用，表明存在独特和共享的致病机制。MSA独特地涉及神经胶质细胞中的氧化解毒过程，而神经元中的囊泡过程在PD/DLB中占主导地位。MSA和PD/DLB之间共享的相互作用，特别是SYNGR3，表明神经元轴突是这两种疾病的起源。总之，我们提供了两种不同突触核蛋白病的αsyn蛋白质相互作用图谱。
