@article{7c931e0767494328806d3ffe0ef209e5,
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.",
keywords = "autophagy, CCL5, CCR5, dementia, Huntington's disease, maraviroc, microglia, mTORC1, neuroinflammation, Tau",
author = "Festa, {Beatrice Paola} and Siddiqi, {Farah H.} and Maria Jimenez-Sanchez and Hyeran Won and Matea Rob and Alvin Djajadikerta and Eleanna Stamatakou and Rubinsztein, {David C.}",
note = "Funding Information: We thank Dr. O. Schwartz (Institut Pasteur, France) for providing HeLa CCR5-GFP cells, Dr. Richard Youle (National Institutes of Health, USA) for providing HeLa CRISPR-Cas9 ATG5 knockout cell lines, Prof. N. Mizushima (University of Tokyo) for providing pEGFP-ATG16L1 and pEGFP-ATG5 plasmids, David Harrison (ALBORADA Drug Discovery Institute, Cambridge) for technical support, and Dr. Claudia Puri for advice and suggestions. We are grateful to Alzheimer's Research UK, the UK Dementia Research Institute (funded by the MRC, Alzheimer's Research UK and the Alzheimer's Society) (to D.C.R.), The Tau Consortium, an anonymous donation to the Cambridge Centre for Parkinson-Plus, the Wellcome Trust (095317/Z/11/Z) and NIHR Cambridge Biomedical Research Center (BRC-1215-20014), European Union's Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie grant agreement no. 860035 (D.C.R. M.R.), and Cambridge Australia Scholarships (to A.D.) for funding. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. B.P.F. M.J.-S. and D.C.R conceived the study. B.P.F. performed the cell biology studies for all the figures except for Figure 1 and extended data 1. M.J.-S. H.W. and M.R. performed the cell biology studies in Figure 1 and extended data 1. A.D. performed the bioinformatics analyses. F.H.S. performed the mouse studies with contributions from B.P.F and E.S. B.P.F. and D.C.R. wrote the first draft of the manuscript and integrated the comments of the other co-authors. D.C.R. supervised the study and was responsible for the funding. D.C.R. is a consultant for Aladdin Healthcare, Technologies Ltd. Mindrank AI, Nido Biosciences, Drishti Discoveries, and PAQ Therapeutics. Funding Information: We thank Dr. O. Schwartz (Institut Pasteur, France) for providing HeLa CCR5-GFP cells, Dr. Richard Youle (National Institutes of Health, USA) for providing HeLa CRISPR-Cas9 ATG5 knockout cell lines, Prof. N. Mizushima (University of Tokyo) for providing pEGFP-ATG16L1 and pEGFP-ATG5 plasmids, David Harrison (ALBORADA Drug Discovery Institute, Cambridge) for technical support, and Dr. Claudia Puri for advice and suggestions. We are grateful to Alzheimer{\textquoteright}s Research UK, the UK Dementia Research Institute (funded by the MRC , Alzheimer{\textquoteright}s Research UK and the Alzheimer{\textquoteright}s Society ) (to D.C.R.), The Tau Consortium , an anonymous donation to the Cambridge Centre for Parkinson-Plus , the Wellcome Trust ( 095317/Z/11/Z ) and NIHR Cambridge Biomedical Research Center ( BRC-1215-20014 ), European Union's Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie grant agreement no. 860035 (D.C.R., M.R.), and Cambridge Australia Scholarships (to A.D.) for funding. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = jul,
day = "5",
doi = "10.1016/j.neuron.2023.04.006",
language = "English",
volume = "111",
pages = "2021--2037.e12",
journal = "Neuron",
issn = "0896-6273",
publisher = "CELL PRESS",
number = "13",
}