Peroxisome-Proliferator-Activated Receptor Gamma Coactivator 1 α Contributes to Dysmyelination in Experimental Models of Huntington's Disease

The peroxisome-proliferator-activated receptor gamma coactivator 1 alpha (PGC1 alpha) has been implicated in the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD). Recent data demonstrating white matter abnormalities in PGC1 alpha knock-out (KO) mice prompted us to examine the role of PGC1 alpha in CNS myelination and its relevance to HD pathogenesis. We found deficient postnatal myelination in the striatum of PGC1 alpha KO mice, accompanied by a decrease in myelin basic protein (MBP). In addition, brain cholesterol, its precursors, and the rate-limiting enzymes for cholesterol synthesis, HMG CoA synthase (HMGCS1) and HMG CoA reductase (HMGCR), were also reduced in PGC1 alpha KO mice. Moreover, knockdown of PGC1 alpha in oligodendrocytes by lentiviral shRNA led to a decrease in MBP, HMGCS1, and Hmgcr mRNAs. Chromatin immunoprecipitations revealed the recruitment of PGC1 alpha to MBP promoter in mouse brain, and PGC1 alpha over-expression increased MBP and SREBP-2 promoter activity, suggesting that PGC1 alpha regulates MBP and cholesterol synthesis at the transcriptional level. Importantly, expression of mutant huntingtin (Htt) in primary oligodendrocytes resulted in decreased expression of PGC1 alpha and its targets HmgcS1, Hmgcr, and MBP. Decreased expression of MBP and deficient myelination were found postnatally and in adult R6/2 mouse model of HD. Diffusion tensor imaging detected white matter abnormalities in the corpus callosum of R6/2 mice, and electron microscopy revealed thinner myelin sheaths and increased myelin periodicity in BACHD [bacterial artificial chromosome (BAC)-mediated transgenic model for Huntington's disease] mice expressing full-length mutant Htt. Together, these data suggest that PGC1 alpha plays a role in postnatal myelination and that deficient PGC1 alpha activity in oligodendrocytes may contribute to abnormal myelination in HD.