| Autor: |
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. |
| Předmět: |
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| Zdroj: |
Journal of Neuroscience; 3/28/2018, Vol. 38 Issue 13, p3273-3286, 14p |
| Abstrakt: |
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. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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