Cell-Specific Deletion of PGC-1 alpha from Medium Spiny Neurons Causes Transcriptional Alterations and Age-Related Motor Impairment

Multiple lines of evidence indicate that a reduction in the expression and function of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) is associated with neurodegeneration in diseases such as Huntington's disease (HD). Polymorphisms in the PGC-1 alpha gene modify HD progression and PGC-1 alpha expression is reduced in striatal medium spiny neurons (MSNs) of HD patients and mouse models. However, neither the MSN-specific function of PGC-1 alpha nor the contribution of PGC-1 alpha deficiency to motor dysfunction is known. We identified novel, PGC-1 alpha -dependent transcripts involved in RNA processing, signal transduction, and neuronal morphology and confirmed reductions in these transcripts in male and female mice lacking PGC-1 alpha specifically in MSNs, indicating a cell-autonomous effect in this population. MSN-specific PGC-1 alpha deletion caused reductions in previously identified neuronal and metabolic PGC-1 alpha-dependent genes without causing striatal vacuolizations. Interestingly, these mice exhibited a hypoactivity with age, similar to several HD animal models. However, these newly identified PGC-1 alpha -dependent genes were upregulated with disease severity and age in knock-in HD mouse models independent of changes in PGC-1 alpha transcript, contrary to what would be predicted from a loss-of-function etiological mechanism. These data indicate that PGC-1 alpha is necessary forMSNtranscriptional homeostasis and function with age and that, whereas PGC-1 alpha loss in MSNs does not replicate an HD-like phenocopy, its downstream genes are altered in a repeat-length and age-dependent fashion. Understanding the additive effects of PGC-1 alpha gene functional variation and mutant huntingtin on transcription in this cell type may provide insight into the selective vulnerability of MSNs in HD.