%0 Journal Article
%T Cell-Specific Deletion of PGC-1¦Á from Medium Spiny Neurons Causes Transcriptional Alterations and Age-Related Motor Impairment
%A David K. Crossman
%A Glenn C. Rowe
%A Jeremy J. Day
%A Laura J. McMeekin
%A Peter J. Detloff
%A Rita M. Cowell
%A Stephanie N. Fox
%A Ye Li
%A Yuqing Li
%J The Journal of Neurosience
%D 2018
%R 10.1523/JNEUROSCI.0848-17.2018
%X Multiple lines of evidence indicate that a reduction in the expression and function of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1¦Á (PGC-1¦Á) is associated with neurodegeneration in diseases such as Huntington's disease ( H D). Polymorphisms in the PGC-1¦Á gene modify HD progression and PGC-1¦Á expression is reduced in striatal medium spiny neurons (MSNs) of HD patients and mouse models. However, neither the MSN-specific function of PGC-1¦Á nor the contribution of PGC-1¦Á deficiency to motor dysfunction is known. We identified novel, PGC-1¦Á-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¦Á specifically in MSNs, indicating a cell-autonomous effect in this population. MSN-specific PGC-1¦Á deletion caused reductions in previously identified neuronal and metabolic PGC-1¦Á-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¦Á-dependent genes were upregulated with disease severity and age in knock-in HD mouse models independent of changes in PGC-1¦Á transcript, contrary to what would be predicted from a loss-of-function etiological mechanism. These data indicate that PGC-1¦Á is necessary for MSN transcriptional homeostasis and function with age and that, whereas PGC-1¦Á 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¦Á gene functional variation and mutant huntingtin on transcription in this cell type may provide insight into the selective vulnerability of MSNs in HD.

SIGNIFICANCE STATEMENT Reductions in peroxisome proliferator-activated receptor gamma coactivator-1¦Á (PGC-1¦Á)-mediated transcription have been implicated in the pathogenesis of Huntington's disease ( H D). We show that, although PGC-1¦Á-dependent transcription is necessary to maintain medium spiny neuron (MSN) function with age, its loss is insufficient to cause striatal atrophy in mice. We also highlight a set of genes that can serve as proxies for PGC-1¦Á functional activity in the striatum for target engagement studies. Furthermore, we demonstrate that PGC-1¦Á-dependent genes are upregulated in a dose- and age-dependent fashion in HD mouse models, contrary to what would be predicted from a loss-of-function etiological mechanism. However, given this role for PGC-1¦Á
%U http://www.jneurosci.org/content/38/13/3273