Unraveling α-synuclein and amylin co-aggregation: pathological insights and biomarker development for Parkinson's disease

• Published in: Theranostics Vol. 15; no. 15; pp. 7409 - 7424
• Main Authors: Zhou, Yuhang, Lai, Minchao, Shu, Bowen, Wang, Benguo, Wang, Dian, Liu, Haoran, Li, Baowan, Guo, Jianhe, Hu, Dongjie, Li, Mingyuan, Zhu, Cheng, Kang, Muzhi, Li, Zhong Alan, Wang, Renzhi, Zhao, Yongjuan, Tuan, Rocky S., Guo, Keying, Li, Chenzhong, Jiang, Cheng
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher 01.01.2025
• Subjects: Aged; alpha-Synuclein - blood; alpha-Synuclein - metabolism; Biomarkers - blood; Biomarkers - metabolism; Brain - metabolism; Brain - pathology; Extracellular Vesicles - metabolism; Female; Humans; Islet Amyloid Polypeptide - blood; Islet Amyloid Polypeptide - metabolism; Male; Middle Aged; Multiple System Atrophy - blood; Multiple System Atrophy - metabolism; Multiple System Atrophy - pathology; Parkinson Disease - blood; Parkinson Disease - diagnosis; Parkinson Disease - metabolism; Parkinson Disease - pathology; Protein Aggregates; Research Paper
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.112396

Patients with diabetes have a higher morbidity in Parkinson's disease (PD) than others, but the mechanism underlying this link remains controversial. The co-aggregation of α-synuclein (α-syn) and amylin has been hypothesized as a key contributor. Molecular interaction analysis and co-immunoprecipitation were conducted to assess the feasibility of co-aggregation. We developed a tailored surface-based fluorescence distribution method to detect the co-aggregate in the subject's serum sample and brain-derived L1CAM-positive Extracellular Vesicles. Subjects include Health Controls (HC), PD patients and multiple system atrophy (MSA) patients. The co-aggregates were detected in PD patient samples, in both serum and brain-derived extracellular vesicles (EVs). We demonstrated that the co-aggregate count could distinguish PD patients from healthy individuals. Our results revealed a positive correlation between co-aggregate count and Parkinson's disease scales or diabetes markers, highlighting the role of co-aggregation in promoting PD progression. The distribution of co-aggregates demonstrated diversity among different α-synucleinopathies; a high co-aggregates count was found in EVs and serum of PD patients, but not in the serum of MSA patients. The existence of α-syn-amylin co-aggregates was confirmed. Our findings suggest that α-syn-amylin co-aggregation may play a pivotal role in PD pathology, and have the potential as a biomarker. These results point to a potential path for early-diagnosis and therapeutic intervention.