Cellular fibronectin exacerbates α-synuclein aggregation via integrin alpha4beta1 mediated PARP1 and SCD elevation
Zifeng Huang1, Hui Zhong1, Yingqiong Lu2
1Department of Neurology, Zhujiang Hospital of Southern Medical University, Guangzhou, Guangdong 510280, PR China.
Summary
Cellular fibronectin (cFn) exacerbates Parkinson's disease pathology by damaging mitochondria and disrupting lipid metabolism through integrin α4β1, leading to α-synuclein aggregation. Targeting cFn may offer a new therapeutic approach for PD.
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Mitochondrial dysfunction and lipid dysregulation are implicated in Parkinson's disease (PD) pathogenesis.
- The role of extracellular matrix components, such as cellular fibronectin (cFn), in PD-related pathological mechanisms is not well understood.
Purpose of the Study:
- To investigate whether cellular fibronectin (cFn) contributes to α-synuclein (α-syn) abnormality in Parkinson's disease (PD).
- To elucidate the mechanisms by which cFn may induce mitochondrial energy depletion and disrupt lipid homeostasis.
Main Methods:
- Utilized 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated PD mouse models and human neuronal SH-SY5Y cells.
- Employed astrocyte-derived cFn delivery and AAV-mediated cFn knockdown models.
- Assessed mitochondrial dysfunction via transmission electron microscopy (TEM) and measured levels of poly (ADP-ribose) polymerase-1 (PARP1), α-syn, and cFn-induced lipid dysmetabolism.
Main Results:
- Excessive cFn accumulation in the substantia nigra pars compacta (SNpc) of MPTP-treated mice correlated with exacerbated neuronal mitochondrial dysfunction and α-syn aggregation.
- cFn activated PARP1 and induced NAD+ depletion via integrin α4β1, promoting α-syn aggregation.
- cFn increased free fatty acids and triglycerides by binding to integrin α4β1, synergistically worsening α-syn abnormality.
- cFn activated stearoyl-CoA desaturase (SCD) via integrin α4β1 interaction.
- Genetic cFn depletion rescued mitochondrial and α-syn pathologies in MPTP-treated mice.
Conclusions:
- Cellular fibronectin (cFn) exacerbates α-syn aggregation in Parkinson's disease through integrin α4β1-mediated activation of PARP1 and SCD.
- These pathways lead to mitochondrial dysfunction and lipid dysmetabolism, contributing to PD progression.
- Targeting cFn presents a potential therapeutic strategy for Parkinson's disease.
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