Affiliation:
1. Neuroscience Paris Seine, Institut de Biologie Paris-Seine (IBPS), CNRS UMR 8246/INSERM U1130, Sorbonne Université, 75005 Paris, France
2. Imaging Facility, Institut de Biologie Paris-Seine (IBPS), Sorbonne Université, 75005 Paris, France
Abstract
Cholesterol metabolism dysregulation is associated with several neurological disorders. In Huntington’s 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 S100β 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.
Funder
Association Francaise Myopathie
Agence Nationale de la Recherche
Centre National de la Recherche Scientifique
Institut National de la Santé et de la Recherche Médicale
Sorbonne Université Faculté des Sciences et Ingénierie
IBPS Imaging Facility
Region-Île-de-France
Sorbonne-University
CNRS
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis