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Immune activation is abundant in the striatum of HD patients. Detection of active microglia at presymptomatic stages suggests that microgliosis is a key early driver of neuronal dysfunction and degeneration. Recent studies showed that deletion of\u00a0\n                      <jats:italic>Tyrobp<\/jats:italic>\n                      , a microglial protein, ameliorates neuronal dysfunction in Alzheimer\u2019s disease amyloidopathy and tauopathy mouse models while decreasing components of the complement subnetwork.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      While TYROBP\/DAP12-mediated microglial activation is detrimental for some diseases such as peripheral nerve injury, it is beneficial for other diseases. We sought to determine whether the TYROBP network is implicated in HD and whether\u00a0\n                      <jats:italic>Tyrobp<\/jats:italic>\n                      \u00a0deletion impacts HD striatal function and transcriptomics.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      To test the hypothesis that\u00a0\n                      <jats:italic>Tyrobp<\/jats:italic>\n                      \u00a0deficiency would be beneficial in an HD model, we placed the Q175 HD mouse model on a\u00a0\n                      <jats:italic>Tyrobp<\/jats:italic>\n                      -null background. We characterized these mice with a combination of behavioral testing, immunohistochemistry, transcriptomic and proteomic profiling. Further, we evaluated the gene signature in isolated Q175 striatal microglia, with and without\u00a0\n                      <jats:italic>Tyrobp.<\/jats:italic>\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Comprehensive analysis of publicly available human HD transcriptomic data revealed that the TYROBP network is overactivated in the HD putamen. The Q175 mice showed morphologic microglial activation, reduced levels of post-synaptic density-95 protein and motor deficits at 6 and 9\u00a0months of age, all of which were ameliorated on the\u00a0\n                      <jats:italic>Tyrobp<\/jats:italic>\n                      -null background. Gene expression analysis revealed that lack of\u00a0\n                      <jats:italic>Tyrobp<\/jats:italic>\n                      \u00a0in the Q175 model does not prevent the decrease in the expression of striatal neuronal genes but reduces pro-inflammatory pathways that are specifically active in HD human brain, including genes identified as detrimental in neurodegenerative diseases, e.g.\n                      <jats:italic>C1q<\/jats:italic>\n                      and members of the\n                      <jats:italic>Ccr5<\/jats:italic>\n                      signaling pathway. Integration of transcriptomic and proteomic data revealed that astrogliosis and complement system pathway were reduced after\u00a0\n                      <jats:italic>Tyrobp<\/jats:italic>\n                      \u00a0deletion, which was further validated by immunofluorescence analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our data provide molecular and functional support demonstrating that\u00a0\n                      <jats:italic>Tyrobp<\/jats:italic>\n                      \u00a0deletion prevents many of the abnormalities in the\u00a0HD Q175 mouse model, suggesting that the\u00a0\n                      <jats:italic>Tyrobp<\/jats:italic>\n                      \u00a0pathway is a potential therapeutic candidate for Huntington\u2019s disease.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-024-03052-4","type":"journal-article","created":{"date-parts":[[2024,3,8]],"date-time":"2024-03-08T09:02:11Z","timestamp":1709888531000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["TYROBP\/DAP12 knockout in Huntington\u2019s disease Q175 mice cell-autonomously decreases microglial expression of disease-associated genes and non-cell-autonomously mitigates astrogliosis and motor deterioration"],"prefix":"10.1186","volume":"21","author":[{"given":"Jordi","family":"Creus-Muncunill","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean Vianney","family":"Haure-Mirande","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniele","family":"Mattei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Bons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angie V.","family":"Ramirez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"B. 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