Fibrinogen exacerbates α-synuclein aggregation and mitochondrial dysfunction via alpha5beta3 integrin in Parkinson's disease

Zifeng Huang; Jialing Zheng; Feilan Yuan; Hui Zhong; Ruoyang Yu; Yuqi Luo; Muwei Zhang; Shuhan Chen; Bibiao Shen; Zhenchao Xie; Wanlin Yang; Shuzhen Zhu; Rongfang Que; Fen Xie; Huanzhu Liu; Weili Yang; Lu Zhang; Wenhua Zheng; Kunlin Jin; Chao Deng; Bin Xiao; Jia Nee Foo; Ling-Ling Chan; Chin-Hsien Lin; Zhi Dong Zhou; Eng-King Tan; Qing Wang

doi:10.1016/j.jare.2025.05.050

Fibrinogen exacerbates α-synuclein aggregation and mitochondrial dysfunction via alpha5beta3 integrin in Parkinson's disease

J Adv Res. 2025 May 25:S2090-1232(25)00370-4. doi: 10.1016/j.jare.2025.05.050. Online ahead of print.

Authors

Zifeng Huang¹, Jialing Zheng¹, Feilan Yuan¹, Hui Zhong¹, Ruoyang Yu¹, Yuqi Luo¹, Muwei Zhang¹, Shuhan Chen², Bibiao Shen¹, Zhenchao Xie¹, Wanlin Yang¹, Shuzhen Zhu¹, Rongfang Que¹, Fen Xie¹, Huanzhu Liu¹, Weili Yang³, Lu Zhang⁴, Wenhua Zheng⁵, Kunlin Jin⁶, Chao Deng⁷, Bin Xiao⁸, Jia Nee Foo⁹, Ling-Ling Chan⁸, Chin-Hsien Lin¹⁰, Zhi Dong Zhou⁸, Eng-King Tan¹¹, Qing Wang¹²

Affiliations

¹ Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510280, PR China.
² Guangdong Experimental High School, Longxi Avenue Shengshi Road No.1, Liwan District, Guangzhou 510000, PR China.
³ Guangdong Key Laboratory of Non-human Primate Research, Guangdong- Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, PR China.
⁴ Key Laboratory of Functional Proteomics of Guangdong Province, Key Laboratory of Mental Health of the Ministry of Education, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, PR China.
⁵ Centre of Reproduction, Development & Aging and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau, PR China.
⁶ Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.
⁷ School of Medical, Indigenous and Health Sciences, and Molecular Horizons, University of Wollongong, Wollongong, Australia.
⁸ Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Duke-NUS Medical School, Singapore.
⁹ Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.
¹⁰ Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
¹¹ Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Duke-NUS Medical School, Singapore. Electronic address: tan.eng.king@sgh.com.sg.
¹² Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510280, PR China. Electronic address: wqdennis@hotmail.com.

PMID: 40425084
DOI: 10.1016/j.jare.2025.05.050

Abstract

Introduction: Blood-brain barrier(BBB) disruption promotes the influx of the fibrinogen(FG); however, it remains unknown whether FG deposit contributes to neurodegeneration in Parkinson's disease(PD).

Objectives: We aimed to examine the pathophysiologic link among FG, mitochondrial dysfunction and α-synuclein(α-syn) abnormality in PD.

Methods: First, plasma FG levels were measured in 60 healthy controls and 60 PD patients. Second, to determine whether FG contributes to PD pathogenesis, FG was injected into the substantia nigra pars compacta(SNpc) of healthy and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-treated PD mice. Meanwhile, intraperitoneal injections of batroxobin were used to deplete FG in the brain of PD mice. Mitochondrial ultrastructure in mouse models was observed by transmission electron microscopy(TEM), and mitochondrial functions in SH-SY5Y cells were examined by different assay kits and flow cytometry. The mechanisms underlying FG-induced α-syn abnormality and mitochondrial dysfunction were observed by RNA sequencing and validated in various experiments including western blot and immunostaining. Last, the endocytosis of FG in primary neurons were detected by confocal microscopy, and α-syn aggregation after FG co-incubation were evaluated by western blot, ThT-binding assay and TEM.

Results: PD patients exhibited elevated levels of FG in peripheral blood compared to HCs, and there was a positive correlation between the plasma FG and PD clinical severity. Excessive FG in the SNpc of MPTP-treated mice promoted poly (ADP-ribose) (PAR) polymerase-1(PARP1) elevation, mediated by the α_vβ₃ integrin receptor. FG exacerbated α-syn abnormalities and mitochondrial dysfunctions via PARP1 activation. Moreover, FG entered neurons by α_vβ₃ integrin mediation, potentially enhancing α-syn fibrillation and toxicity. FG facilitated α-syn aggregation subsequently reduced ATP-dependent Clp protease(ClpP) level, impairing neuronal mitochondrial unfolded response and increasing mitochondrial ROS. Pharmacological depletion of FG by batroxobin ameliorated neurodegeneration in MPTP-treated mice.

Conclusion: Our study indicate that FG plays an essential pathological role in α-syn abnormality. FG-targeting therapy can be a promising strategy against neurodegeneration in PD.

Keywords: Fibrinogen; Mitochondrial dysfunction; Parkinson’s disease; α-Synuclein.