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

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