Fibrinogen exacerbates α-synuclein aggregation and mitochondrial dysfunction via alpha5beta3 integrin in Parkinson's disease.
Fibrinogen exacerbates α-synuclein aggregation and mitochondrial dysfunction via alpha5beta3 integrin in Parkinson's disease.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Guangzhou, CN · Author affiliation
Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510280, PR China.Location evidence
Longxi, CN · Author affiliation
Guangdong Experimental High School, Longxi Avenue Shengshi Road No.1, Liwan District, Guangzhou 510000, PR China.Location evidence
Jinan, CN · Author affiliation
Guangdong Key Laboratory of Non-human Primate Research, Guangdong- Hongkong-Macau Institute of CNS Regeneration, Jinan University, Guangzhou 510632, PR China.Location evidence
CN · Author affiliation · country only
Centre of Reproduction, Development & Aging and Institute of Translation Medicine, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau, PR China.Location evidence
Fort Worth, US · Author affiliation
Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, Fort Worth, TX 76107, USA.Location evidence
Wollongong, AU · Author affiliation
School of Medical, Indigenous and Health Sciences, and Molecular Horizons, University of Wollongong, Wollongong, Australia.Location evidence
Singapore, SG · Author affiliation
Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Duke-NUS Medical School, Singapore.Location evidence
Taipei, TW · Author affiliation
Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.Location evidence
A plain-language reading has not been prepared for this paper yet.
Original 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 αvβ3 integrin receptor. FG exacerbated α-syn abnormalities and mitochondrial dysfunctions via PARP1 activation. Moreover, FG entered neurons by αvβ3 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.