Affiliations: [a] Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA
| [b] Department of Neurology, Vanderbilt University Medical Center, Nashville, TN, USA
| [c] Vanderbilt Center in Molecular Toxicology, Vanderbilt University Medical Center, Nashville, TN, USA
| [d] Department of Chemistry, Vanderbilt University, Nashville, TN, USA
| [e] Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN, USA
| [f] Vanderbilt Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN, USA
| [g] Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN, USA
| [h] School of Health Sciences, Purdue University, West Lafayette, IN, USA
Correspondence to: Aaron B. Bowman, 550 Stadium Mall Drive – HAMP 1173A, West Lafayette, IN 47907-2051, USA. Tel.: +1 765 494 2684; E-mail: [email protected].
Note:  These authors contributed equally to this work.
Abstract: Background:Cholesterol is necessary for proper neurodevelopment and neuronal health. The brain relies on neural and astrocytic de novo cholesterol synthesis. Huntington’s disease presents with altered levels of cholesterol precursors however it is unknown when the disruption in this molecular pathway occurs and whether Manganese (Mn) may alter these metabolic alterations. Objective:To examine the effect of Mn exposure on cholesterol biosynthesis in pre-manifest and manifest Huntington’s disease mice. Methods:12-week (pre-manifest) male and female and 42-week old (manifest) female YAC128 and littermate control (WT) mice received 3 subcutaneous Mn or vehicle injections. Animals were sacrificed 24 hours after the final injection and striatum, cerebral cortex and cerebellum were collected to measure cholesterol and cholesterol precursors using LC/MS-MS. Results:Striatal desmosterol and cholesterol are increased in pre-manifest HD females compared to age-matched WT female mice. Striatal lanosterol, 8-DHC and desmosterol and cholesterol are reduced in manifest HD females compared to age-and sex-matched WT mice with minimal effects in the cortex and cerebellum. Mn treatment had no effect in the pre-manifest or manifest female brain except reduced lanosterol levels in the cortex of pre-manifest female mice. Neither Mn or HD altered brain cholesterol precursor levels in the pre-manifest HD or WT male mouse. Conclusions:Cholesterol biosynthesis is impaired in early disease stage in female HD mice only and continues throughout disease. These alterations appear largely striatal-specific. Acute systemic exposure to Mn did not significantly alter cholesterol biosynthesis in the striatum at any disease stage.