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- Title
Cell-Specific Deletion of PGC-Iα from Medium Spiny Neurons Causes Transcriptional Alterations and Age-Related Motor Impairment.
- Authors
McMeekin, Laura J.; Ye Li; Fox, Stephanie N.; Rowe, Glenn C.; Crossman, David K.; Day, Jeremy J.; Yuqing Li; Detloff, Peter J.; Cowell, Rita M.
- Abstract
Multiple lines of evidence indicate that a reduction in the expression and function of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1a(PGC-lα) is associated with neurodegeneration in diseases such as Huntington's disease (HD). Polymorphisms in the PGC-lα gene modify HD progression and PGC-lα expression is reduced in striatal medium spiny neurons (MSNs) of HD patients and mouse models. However, neither the MSN-specific function of PGC-lα nor the contribution of PGC-lα deficiency to motor dysfunction is known. We identified novel, PGC-lα-dependent transcripts involved in RNA processing, signal transduction, and neuronal morphology and confirmed reductions in these transcripts in male and female mice lacking PGC-lα specifically in MSNs, indicating a cell-autonomous effect in this populαtion. MSN-specific PGC-lα deletion caused reductions in previously identified neuronal and metabolic PGC-lα-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-lα-dependent genes were upregulated with disease severity and age in knock-in HD mouse models independent of changes in PGC-lα transcript, contrary to what would be predicted from a loss-of-function etiological mechanism. These data indicate that PGC-1 a is necessary for MSN transcriptional homeostasis and function with age and that, whereas PGC-lα 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 a gene functional variation and mutant huntingtin on transcription in this cell type may provide insight into the selective vulnerability of MSNs in HD.
- Subjects
NEURONS; HUNTINGTON disease; CELLULAR signal transduction; NEURODEGENERATION; GENETIC transcription
- Publication
Journal of Neuroscience, 2018, Vol 38, Issue 13, p3273
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.0848-17.2018