2. Academic Validation
  3. Fibrinogen degradation products exacerbate alpha-synuclein aggregation by inhibiting autophagy via downregulation of Beclin1 in multiple system atrophy

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

  • Neurotherapeutics. 2025 Feb 3:e00538. doi: 10.1016/j.neurot.2025.e00538.
Huanzhu Liu 1,  Ruoyang Yu 1,  Muwei Zhang 1,  Xiaoyan Zheng 2,  Lizi Zhong 1,  Wanlin Yang 1,  Yuqi Luo 1,  Zifeng Huang 1,  Jialing Zheng 1,  Hui Zhong 1,  Xiaobo Wei 1,  Wenhua Zheng 3,  Yinghua Yu 4,  Qing Wang 5
Affiliations

Affiliations

  • 1 Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, China.
  • 2 School of Rehabilitation Sciences, Southern Medical University, Guangzhou, China.
  • 3 Department of Pharmaceutical Sciences, Faculty of Health Sciences, University of Macau, Taipa, 999078, Macao, China.
  • 4 School of Medical, Indigenous and Health Sciences, University of Wollongong, Wollongong, NSW, Australia. Electronic address: yinghua@uow.edu.au.
  • 5 Department of Neurology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510282, China. Electronic address: wqdennis@hotmail.com.
PMID: 39904669 DOI: 10.1016/j.neurot.2025.e00538
Abstract

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

Keywords

Autophagy; Beclin1; Fibrinogen; Fibrinogen degradation products; Multiple system atrophy; Oligodendrocyte.

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