I06 SREBP2 delivery to striatal astrocytes normalizes transcription of cholesterol biosynthesis genes and ameliorates pathological features in huntington’s disease

Background Cholesterol is a multifaceted molecule essential for brain function (Martin 2014). In the adult brain, cholesterol is produced locally by astrocytes and transferred to neurons through apoE-containing lipoproteins (Jurevics & Morell 1995; Mauch 2001). Disruption of brain cholesterol pathways has been linked to several neurological disorders, including Huntington’s disease (HD), a genetic, neurodegenerative disorder caused by a CAG expansion in the gene encoding the Huntingtin protein (Valenza & Cattaneo 2011). Brain cholesterol biosynthesis and content are reduced in several HD models (Valenza 2005; 2007; 2010; Shankaran 2017). The underlying molecular mechanism relies on reduced nuclear translocation of SREBP2, the transcription factor that controls the transcription of several genes involved in cholesterol biosynthesis (Valenza 2015; Di Pardo 2020). We have recently shown that cholesterol supplementation to the brain, with different delivery systems, ameliorates synaptic and behavioral defects in the R6/2 mouse model (Valenza 2015; Birolini 2020; Birolini 2021). Aims and Methods Here, we used recombinant adeno-associated virus 2/5 to deliver exogenous SREBP2 specifically in astrocytes in order to enhance the endogenous cholesterol biosynthesis in the striatum of R6/2 mice. Results We found that exogenous SREBP2 stimulates the transcription of key cholesterol biosynthesis genes resulting in fully restoration of synaptic transmission, reversal of Drd2 transcript levels, clearance of mutant Huntingtin (muHTT) aggregates and rescue of behavioral deficits. Conclusions These results demonstrate that stimulating cholesterol biosynthesis in striatal astrocytes has a positive effect on behavioral decline and disease-related phenotypes in HD mice. Furthermore, we have demonstrated that glial SREBP2 participates in HD pathogenesis in vivo, highlighting the translational potential of cholesterol-based strategies for this disease.