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In Huntington\u2019s disease (HD), several enzymes involved in cholesterol metabolism are downregulated, among which the neuronal cholesterol 24-hydroxylase, CYP46A1, is of particular interest. The restoration of CYP46A1 expression in striatal neurons of HD mouse models is beneficial for motor behavior, cholesterol metabolism, transcriptomic activity, and alleviates neuropathological hallmarks induced by mHTT. Among the genes regulated after CYP46A1 restoration, those involved in cholesterol synthesis and efflux may explain the positive effect of CYP46A1 on cholesterol precursor metabolites. Since cholesterol homeostasis results from a fine-tuning between neurons and astrocytes, we quantified the distribution of key genes regulating cholesterol metabolism and efflux in astrocytes and neurons using in situ hybridization coupled with S100\u03b2 and NeuN immunostaining, respectively. Neuronal expression of CYP46A1 in the striatum of HD zQ175 mice increased key cholesterol synthesis driver genes (Hmgcr, Dhcr24), specifically in neurons. This effect was associated with an increase of the srebp2 transcription factor gene that regulates most of the genes encoding for cholesterol enzymes. However, the cholesterol efflux gene, ApoE, was specifically upregulated in astrocytes by CYP46A1, probably though a paracrine effect. In summary, the neuronal expression of CYP46A1 has a dual and specific effect on neurons and astrocytes, regulating cholesterol metabolism. The neuronal restoration of CYP46A1 in HD paves the way for future strategies to compensate for mHTT toxicity.<\/jats:p>","DOI":"10.3390\/ijms241311001","type":"journal-article","created":{"date-parts":[[2023,7,3]],"date-time":"2023-07-03T00:34:08Z","timestamp":1688344448000},"page":"11001","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cell-Type Specific Regulation of Cholesterogenesis by CYP46A1 Re-Expression in zQ175 HD Mouse Striatum"],"prefix":"10.3390","volume":"24","author":[{"given":"Katleen","family":"Pinchaud","sequence":"first","affiliation":[{"name":"Neuroscience Paris Seine, Institut de Biologie Paris-Seine (IBPS), CNRS UMR 8246\/INSERM U1130, Sorbonne Universit\u00e9, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chlo\u00e9","family":"Masson","sequence":"additional","affiliation":[{"name":"Neuroscience Paris Seine, Institut de Biologie Paris-Seine (IBPS), CNRS UMR 8246\/INSERM U1130, Sorbonne Universit\u00e9, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baptiste","family":"Dayre","sequence":"additional","affiliation":[{"name":"Neuroscience Paris Seine, Institut de Biologie Paris-Seine (IBPS), CNRS UMR 8246\/INSERM U1130, Sorbonne Universit\u00e9, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Coline","family":"Mounier","sequence":"additional","affiliation":[{"name":"Neuroscience Paris Seine, Institut de Biologie Paris-Seine (IBPS), CNRS UMR 8246\/INSERM U1130, Sorbonne Universit\u00e9, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3116-7685","authenticated-orcid":false,"given":"Jean-Fran\u00e7ois","family":"Gilles","sequence":"additional","affiliation":[{"name":"Imaging Facility, Institut de Biologie Paris-Seine (IBPS), Sorbonne Universit\u00e9, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Vanhoutte","sequence":"additional","affiliation":[{"name":"Neuroscience Paris Seine, Institut de Biologie Paris-Seine (IBPS), CNRS UMR 8246\/INSERM U1130, Sorbonne Universit\u00e9, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jocelyne","family":"Caboche","sequence":"additional","affiliation":[{"name":"Neuroscience Paris Seine, Institut de Biologie Paris-Seine (IBPS), CNRS UMR 8246\/INSERM U1130, Sorbonne Universit\u00e9, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandrine","family":"Betuing","sequence":"additional","affiliation":[{"name":"Neuroscience Paris Seine, Institut de Biologie Paris-Seine (IBPS), CNRS UMR 8246\/INSERM U1130, Sorbonne Universit\u00e9, 75005 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"552","DOI":"10.1002\/1531-8257(200005)15:3<552::AID-MDS1020>3.0.CO;2-P","article-title":"Rate of Caudate Atrophy in Presymptomatic and Symptomatic Stages of Huntington\u2019s Disease","volume":"15","author":"Aylward","year":"2000","journal-title":"Mov. 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