A search to validate a peripheral biomarker of neurodegeneration in Huntington disease and new insights in the pathogenesis

Huntington’s disease (HD) is caused by a dominant polyglutamine expansion within the N-terminus of the huntingtin protein. The mutant protein gains a toxic function and transcriptional dysregulation, proteasome impairment and mitochondrial dysfunction are among the main processes leading to cell death of striatal and cortical neurons. Quantitative MRI scans of the striatum are used to follow disease progression, but biomarkers for clinical trials of potential disease-modifying therapies have not been identified yet. We found that brain cholesterol biosynthesis was significantly reduced in several HD mouse models, and in brain and fibroblasts of HD patients. We also found that the brain originated metabolite 24S-hydroxycholesterol (24OHC), which crosses the blood brain barrier and can be measured in blood, was decreased in HD patients’ plasma, and HD mice’s brain and plasma. The brain cholesterol homeostasis is maintained through the conversion of cholesterol by the neuronal-specific cholesterol 24-hydroxylases: the levels of 24OHC in the circulation reflect the number of metabolically active neurons and thus the volume of the brain grey matter. The aims of this proposal are: a) to validate the value of 24OHC as a quantitative biomarker of neurodegeneration in human disease by an international longitudinal study; b) to gather further information on the underlying molecular mechanism in HD mouse models.