{"doi":"10.1016/j.neuron.2023.04.006","title":"Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration","abstract":"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.","journal":"Neuron","year":2023,"id":316020,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":120,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.952,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1018605,"name":"Farah H. Siddiqi","orcid":"0000-0001-9185-0163","position":1,"is_corresponding":false},{"id":1018606,"name":"María Jiménez-Sánchez","orcid":"0000-0002-2287-1582","position":2,"is_corresponding":false},{"id":137918,"name":"Hyeran Won","orcid":null,"position":3,"is_corresponding":false},{"id":1019282,"name":"Matea Rob","orcid":null,"position":4,"is_corresponding":false},{"id":1018607,"name":"Alvin Djajadikerta","orcid":"0000-0002-6827-2817","position":5,"is_corresponding":false},{"id":1018608,"name":"Eleanna Stamatakou","orcid":"0000-0002-0665-9979","position":6,"is_corresponding":false},{"id":281828,"name":"David C. Rubinsztein","orcid":"0000-0001-5002-5263","position":7,"is_corresponding":false},{"id":506622,"name":"Beatrice Paola Festa","orcid":"0009-0007-7761-7403","position":0,"is_corresponding":true}],"reference_count":75,"raw_metadata":null,"created_at":"2026-07-19T01:06:32.274501Z","pmid":"37105172","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}