Fibrinogen degradation products exacerbate alpha-synuclein aggregation by inhibiting autophagy via downregulation of Beclin1 in multiple system atrophy

• DOI: 10.1016/j.neurot.2025.e00538
• Publication Date: 2025-02-04T04:22:38Z
• Authors: Huanzhu Liu; Ruoyang Yu; Muwei Zhang; Xiaoyan Zheng; Lizi Zhong; Wanlin Yang; Yuqi Luo; Zifeng Huang; Jialing Zheng; Hui Zhong; Xiaobo Wei; Wenhua Zheng; Yinghua Yu; Qing Wang
• Keywords: Degradation; Protein Degradation; Alpha (finance)

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease arising from accumulation of the α-synuclein and aberrant protein clearance in oligodendrocytes. The mechanisms autophagy involved progression MSA remain poorly understood. It reported that patients have blood-brain barrier impairments, which may increase entry fibrinogen into brain. However, roles its degradation products (FDPs) on unknown. Here, we established animal model by intraperitoneal injection 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) 3-nitropropionic acid (3-NP), cellular models adding fibrillar α-syn oligodendrocytes to investigate FDPs We found inhibit lysosomes for degradation, increasing aggregation (OLN-93). Our findings indicated OLN-93, inhibited expressions Beclin1 Bif-1, could promote fusion autophagosomes with lysosomes. Furthermore, expression was elevated FDPs-injected mice, accompanied an level p62. detected striatum mice. Finally, led autophagic increased phospho-α-synuclein study illustrates can cause inhibiting Beclin1-mediated autophagy, exacerbate progression. These results provide new therapeutic approach MSA, targets inhibitory effect oligodendrocyte autophagy.