CNTNAP4 partial deficiency exacerbates α -synuclein pathology through astrocyte–microglia interplay

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Abstract BackgroundParkinson’s disease (PD) is a common progressive neurodegenerative movement disorder, which is characterized by dopaminergic (DA) neuron death and the aggregation of neurotoxic α-synuclein. CNTNAP4, a risk gene of autism, has been implicated to participate in DA neuron degeneration in PD pathogenesis. However, the role of CNTNAP4 in α-synuclein pathology remains unclear. MethodsHeterozygous CNTNAP4 null mice injected with adeno-associated viral vector (AAV)-mediated human α-synuclein (AAV-hα-Syn) were used to evaluate the impact of partial CNTNAP4 loss on α-synuclein pathology. The resulting physiological/behavioral effects were assessed using behavioral tests, western blotting, immunohistochemistry, and transmission electron microscopy. The underlying mechanism was studied using RNA-sequencing. Cytokine expression and secretion were examined using quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Magnetic Luminex assay kit.ResultsHere we showed CNTNAP4 partial deficiency exacerbates α-synuclein pathology, nigrostriatal DA neuron degeneration and motor impairment, induced by AAV-hα-Syn overexpression. Mechanistically, aggravated α-synuclein pathology stimulates complement C3 release by astrocytes, activating microglial C3a receptor, which in turn triggers microglia to secrete complement C1q and pro-inflammatory cytokines. The astrocyte–microglia crosstalk further drives DA neuron death and motor dysfunction in PD. Furthermore, we showed that in vivo depletion of microglia rescues the aggravated α-synuclein pathology resulting from partial loss of CNTNAP4. ConclusionsOur results indicate that CNTNAP4 plays a key role in α-synuclein pathogenesis by regulating glial crosstalk and may be a potential target for PD treatment.

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