Astrocytic HMGCR-Mediated Cholesterol Alleviated Parkinson's Disease Phenotypes by Inhibiting NF-κB Neuroinflammation

In recent years, the association between abnormal cholesterol metabolism and Parkinson's disease (PD) has attracted considerable attention, but the specific mechanism remains controversial. First, we used Mendelian Randomization (MR) analysis to clarify the relationship between cholesterol and PD. Subsequently, scRNA-seq and RNA-seq were used to identify the crucial role of astrocyte 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) in this process. Moreover, we verified its downstream target genes by RNA-seq, in vivo and in vitro experiments. The upstream transcriptional regulator of HMGCR was identified by database and validated by luciferase reporter and siRNA knockdown assays. The results of the MR analysis showed that low cholesterol levels may increase the risk of PD. This phenomenon was also observed in the PD mouse model. The scRNA-seq and RNA-seq results showed that astrocyte HMGCR played an important role in PD. Increasing astrocytic HMGCR alleviated cholesterol level and PD-related phenotypes. Mechanistically, astrocytic HMGCR-mediated cholesterol alleviated PD phenotypes by inhibiting Nuclear Factor Kappa-B (NF-κB) neuroinflammation. Furthermore, knocking down Forkhead Box O1 (FOXO1) restored HMGCR expression and cholesterol levels, subsequently inhibiting NF-κB activation. Our research indicated that the cholesterol synthesis disorder in astrocytes driven by HMGCR can exacerbate the pathogenesis of PD by promoting neuroinflammation. Targeting HMGCR in astrocytes will be a potential therapeutic approach.