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Cellular Fibronectin Exacerbates Α-Synuclein Aggregation via Integrin Alpha4beta1 Mediated PARP1 and SCD Elevation
Background: Mitochondrial dysfunction and lipid metabolic disturbance may promote pathologic α-synuclein(α-syn) aggregation, accelerating the progression of Parkinson’s disease(PD). Whether extracellular matrices are associated with those pathological mechanisms in PD remains elusive. Here, we aimed to identify if cellular fibronectin (cFn), a component of extracellular matrices, contributes to α-syn abnormality via inducing mitochondrial energy depletion or disrupting lipid homeostasis.
Methods: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-treated PD mice and human SH-SY5Y cell was used. cFn and adeno-associated virus (AAV) was respectively injected into the SNpc and lateral ventricles in mice. Mitochondrial dysfunction was detected by transmission electron microscopy(TEM). The level of poly(ADP‒ribose)(PAR) polymerase-1(PARP1), pathologic α-syn and cFn-induced lipid dysmetabolism was determined.
Results: We observed an increased Fn in brains of PD patients by GEO database analysis and verified Fn accumulation in the SNpc of MPTP-treated mice. Our studies demonstrated that cFn, rather than plamsa Fn(pFn), exacerbated mitochondrial dysfunction and α-syn accumulation in vitro. Mechanically, cFn induced PARP1 activation via integrin α4β1, which contributed to neuronal NAD+ depletion and pathologic α-syn aggregation. Furthermore, cFn induced an increase in FAs and triglycerides(TAGs) in neurons by binding to integrin α4β1, which synergistically contributed to α-syn abnormality. We revealed that cFn induced stearoyl-CoA desaturase(SCD) activation via integrin α4β1, which are interacted with SCD. Genetically depleting cFn suppressed PARP1 activation and SCD elevation, which further rescued the mitochondrial disruption and α-syn abnormalities in MPTP-treated mice.
Conclusions: Our findings suggest that cFn exacerbates α-syn aggregation via integrin α4β1-mediated PARP1 and SCD elevation. cFn-targeting therapy may be a promising strategy for treating PD.
Funding: This work was supported by the National Natural Science Foundation of China (NO: 82071414, 82471433, QW), Scientific Research Foundation of Guangzhou (NO: 202206010005, QW), Science and Technology Program of Guangdong of China (NO: 2020A0505100037, QW), National Medical Research Council (STaR and PD LCG 000207, EKT).
Declaration of Interest: None to declare.
Ethical Approval: All animal experiments were approved by the Experimental Animal Ethics Committee of Zhujiang Hospital of Southern Medical University (Approval No. LAEC 2020-052).
Huang, Zifeng and Zhang, Muwei and Zhong, Hui and Zheng, Jialing and Yu, Ruoyang and Xiao, Bin and Zhou, Zhidong and Yu, Yinghua and Deng, Chao and Jin, Kunlin and Zhu, Shuzhen and Lin, Chin-Hsien and Wu, Yih-Ru and Li, Chong and Domaszewicz, Karolina Poplawska and Tan, Louis C. S. and Chaudhuri, K. Ray and Tan, Eng-King and Wang, Dennis Qing, Cellular Fibronectin Exacerbates Α-Synuclein Aggregation via Integrin Alpha4beta1 Mediated PARP1 and SCD Elevation. Available at SSRN: https://ssrn.com/abstract=4976348 or http://dx.doi.org/10.2139/ssrn.4976348
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