| First Author | Festa BP | Year | 2023 |
| Journal | Neuron | Volume | 111 |
| Issue | 13 | Pages | 2021-2037.e12 |
| PubMed ID | 37105172 | Mgi Jnum | J:341030 |
| Mgi Id | MGI:7489494 | Doi | 10.1016/j.neuron.2023.04.006 |
| Citation | Festa BP, et al. (2023) Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration. Neuron |
| abstractText | In neurodegenerative diseases, microglia switch to an activated state, which results in excessive secretion of pro-inflammatory factors. Our work aims to investigate how this paracrine signaling affects neuronal function. Here, we show that activated microglia mediate non-cell-autonomous inhibition of neuronal autophagy, a degradative pathway critical for the removal of toxic, aggregate-prone proteins accumulating in neurodegenerative diseases. We found that the microglial-derived CCL-3/-4/-5 bind and activate neuronal CCR5, which in turn promotes mTORC1 activation and disrupts autophagy and aggregate-prone protein clearance. CCR5 and its cognate chemokines are upregulated in the brains of pre-manifesting mouse models for Huntington's disease (HD) and tauopathy, suggesting a pathological role of this microglia-neuronal axis in the early phases of these diseases. CCR5 upregulation is self-sustaining, as CCL5-CCR5 autophagy inhibition impairs CCR5 degradation itself. Finally, pharmacological or genetic inhibition of CCR5 rescues mTORC1 hyperactivation and autophagy dysfunction, which ameliorates HD and tau pathologies in mouse models. |
