Peroxisome-proliferator-activated receptor gamma coactivator 1 α contributes to dysmyelination in experimental models of Huntington's disease

J Neurosci. 2011 Jun 29;31(26):9544-53. doi: 10.1523/JNEUROSCI.1291-11.2011.


The peroxisome-proliferator-activated receptor gamma coactivator 1 α (PGC1α) has been implicated in the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD). Recent data demonstrating white matter abnormalities in PGC1α knock-out (KO) mice prompted us to examine the role of PGC1α in CNS myelination and its relevance to HD pathogenesis. We found deficient postnatal myelination in the striatum of PGC1α 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 PGC1α KO mice. Moreover, knockdown of PGC1α in oligodendrocytes by lentiviral shRNA led to a decrease in MBP, HMGCS1, and Hmgcr mRNAs. Chromatin immunoprecipitations revealed the recruitment of PGC1α to MBP promoter in mouse brain, and PGC1α over-expression increased MBP and SREBP-2 promoter activity, suggesting that PGC1α regulates MBP and cholesterol synthesis at the transcriptional level. Importantly, expression of mutant huntingtin (Htt) in primary oligodendrocytes resulted in decreased expression of PGC1α 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 PGC1α plays a role in postnatal myelination and that deficient PGC1α activity in oligodendrocytes may contribute to abnormal myelination in HD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Blotting, Western
  • Brain / metabolism
  • Brain / pathology
  • Chromatin Immunoprecipitation
  • Demyelinating Diseases / genetics
  • Demyelinating Diseases / metabolism*
  • Demyelinating Diseases / pathology
  • Diffusion Tensor Imaging
  • Disease Models, Animal
  • Huntington Disease / genetics
  • Huntington Disease / metabolism*
  • Huntington Disease / pathology
  • Hydroxymethylglutaryl CoA Reductases / genetics
  • Hydroxymethylglutaryl CoA Reductases / metabolism
  • Hydroxymethylglutaryl-CoA Synthase / genetics
  • Hydroxymethylglutaryl-CoA Synthase / metabolism
  • Immunohistochemistry
  • Mice
  • Mice, Knockout
  • Myelin Basic Protein / genetics
  • Myelin Basic Protein / metabolism
  • Myelin Sheath / metabolism*
  • Myelin Sheath / pathology
  • Oligodendroglia / metabolism*
  • Oligodendroglia / pathology
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • Myelin Basic Protein
  • Transcription Factors
  • peroxisome-proliferator-activated receptor-gamma coactivator-1
  • Hydroxymethylglutaryl CoA Reductases
  • Hydroxymethylglutaryl-CoA Synthase