{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T04:39:31Z","timestamp":1774413571730,"version":"3.50.1"},"reference-count":54,"publisher":"Society for Neuroscience","issue":"13","license":[{"start":{"date-parts":[[2018,9,28]],"date-time":"2018-09-28T00:00:00Z","timestamp":1538092800000},"content-version":"vor","delay-in-days":212,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J. Neurosci."],"published-print":{"date-parts":[[2018,3,28]]},"abstract":"<jats:p>Multiple lines of evidence indicate that a reduction in the expression and function of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1\u03b1 (PGC-1\u03b1) is associated with neurodegeneration in diseases such as Huntington's disease (<jats:italic>H<\/jats:italic>D). Polymorphisms in the PGC-1\u03b1 gene modify HD progression and PGC-1\u03b1 expression is reduced in striatal medium spiny neurons (MSNs) of HD patients and mouse models. However, neither the MSN-specific function of PGC-1\u03b1 nor the contribution of PGC-1\u03b1 deficiency to motor dysfunction is known. We identified novel, PGC-1\u03b1-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\u03b1 specifically in MSNs, indicating a cell-autonomous effect in this population. MSN-specific PGC-1\u03b1 deletion caused reductions in previously identified neuronal and metabolic PGC-1\u03b1-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\u03b1-dependent genes were upregulated with disease severity and age in knock-in HD mouse models independent of changes in PGC-1\u03b1 transcript, contrary to what would be predicted from a loss-of-function etiological mechanism. These data indicate that PGC-1\u03b1 is necessary for MSN transcriptional homeostasis and function with age and that, whereas PGC-1\u03b1 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\u03b1 gene functional variation and mutant huntingtin on transcription in this cell type may provide insight into the selective vulnerability of MSNs in HD.<\/jats:p><jats:p><jats:bold>SIGNIFICANCE STATEMENT<\/jats:bold>Reductions in peroxisome proliferator-activated receptor gamma coactivator-1\u03b1 (PGC-1\u03b1)-mediated transcription have been implicated in the pathogenesis of Huntington's disease (<jats:italic>H<\/jats:italic>D). We show that, although PGC-1\u03b1-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\u03b1 functional activity in the striatum for target engagement studies. Furthermore, we demonstrate that PGC-1\u03b1-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\u03b1 in MSN transcriptional homeostasis, it is important to consider how genetic variation in PGC-1\u03b1 could contribute to mutant-huntingtin-induced cell death and disease progression.<\/jats:p>","DOI":"10.1523\/jneurosci.0848-17.2018","type":"journal-article","created":{"date-parts":[[2018,2,28]],"date-time":"2018-02-28T14:15:59Z","timestamp":1519827359000},"page":"3273-3286","source":"Crossref","is-referenced-by-count":20,"title":["Cell-Specific Deletion of PGC-1\u03b1 from Medium Spiny Neurons Causes Transcriptional Alterations and Age-Related Motor Impairment"],"prefix":"10.1523","volume":"38","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2415-3947","authenticated-orcid":false,"given":"Laura 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