| First Author | Zhang W | Year | 2023 |
| Journal | Cell Death Dis | Volume | 14 |
| Issue | 4 | Pages | 285 |
| PubMed ID | 37087484 | Mgi Jnum | J:335251 |
| Mgi Id | MGI:7467623 | Doi | 10.1038/s41419-023-05807-y |
| Citation | Zhang W, et al. (2023) Cntnap4 partial deficiency exacerbates alpha-synuclein pathology through astrocyte-microglia C3-C3aR pathway. Cell Death Dis 14(4):285 |
| abstractText | Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder, which is characterized by dopaminergic (DA) neuron death and the aggregation of neurotoxic alpha-synuclein. Cntnap4, a risk gene of autism, has been implicated to participate in PD pathogenesis. Here we showed Cntnap4 lacking exacerbates alpha-synuclein pathology, nigrostriatal DA neuron degeneration and motor impairment, induced by injection of adeno-associated viral vector (AAV)-mediated human alpha-synuclein overexpression (AAV-halpha-Syn). This scenario was further validated in A53T alpha-synuclein transgenic mice injected with AAV-Cntnap4 shRNA. Mechanistically, alpha-synuclein derived from damaged DA neuron stimulates astrocytes to release complement C3, activating microglial C3a receptor (C3aR), which in turn triggers microglia to secrete complement C1q and pro-inflammatory cytokines. Thus, the astrocyte-microglia crosstalk further drives DA neuron death and motor dysfunction in PD. Furthermore, we showed that in vivo depletion of microglia and microglial targeted delivery of a novel C3aR antagonist (SB290157) rescue the aggravated alpha-synuclein pathology resulting from Cntnap4 lacking. Together, our results indicate that Cntnap4 plays a key role in alpha-synuclein pathogenesis by regulating glial crosstalk and may be a potential target for PD treatment. |
