Department of Neuroscience, Southern Research, Birmingham, Alabama, 35205, and Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham, AL 35294.
Department of Medicine.
J Neurosci. 2018 Mar 28;38(13):3273-3286. doi: 10.1523/JNEUROSCI.0848-17.2018. Epub 2018 Feb 28.
Multiple lines of evidence indicate that a reduction in the expression and function of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is associated with neurodegeneration in diseases such as Huntington's disease (D). Polymorphisms in the PGC-1α gene modify HD progression and PGC-1α expression is reduced in striatal medium spiny neurons (MSNs) of HD patients and mouse models. However, neither the MSN-specific function of PGC-1α nor the contribution of PGC-1α deficiency to motor dysfunction is known. We identified novel, PGC-1α-dependent transcripts involved in RNA processing, signal transduction, and neuronal morphology and confirmed reductions in these transcripts in male and female mice lacking PGC-1α specifically in MSNs, indicating a cell-autonomous effect in this population. MSN-specific PGC-1α deletion caused reductions in previously identified neuronal and metabolic PGC-1α-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-1α-dependent genes were upregulated with disease severity and age in knock-in HD mouse models independent of changes in PGC-1α transcript, contrary to what would be predicted from a loss-of-function etiological mechanism. These data indicate that PGC-1α is necessary for MSN transcriptional homeostasis and function with age and that, whereas PGC-1α 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-1α gene functional variation and mutant huntingtin on transcription in this cell type may provide insight into the selective vulnerability of MSNs in HD. Reductions in peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α)-mediated transcription have been implicated in the pathogenesis of Huntington's disease (D). We show that, although PGC-1α-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-1α functional activity in the striatum for target engagement studies. Furthermore, we demonstrate that PGC-1α-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-1α in MSN transcriptional homeostasis, it is important to consider how genetic variation in PGC-1α could contribute to mutant-huntingtin-induced cell death and disease progression.
多种证据表明，转录共激活因子过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC-1α）的表达和功能降低与亨廷顿病（D）等疾病中的神经退行性变有关。PGC-1α 基因的多态性改变了 HD 的进展，HD 患者和小鼠模型的纹状体中型棘突神经元（MSNs）中 PGC-1α 的表达减少。然而，PGC-1α 在 MSNs 中的特异性功能以及 PGC-1α 缺乏对运动功能障碍的贡献尚不清楚。我们鉴定了涉及 RNA 加工、信号转导和神经元形态的新型 PGC-1α 依赖性转录本，并在缺乏 PGC-1α 的雄性和雌性小鼠中证实了这些转录本的减少，这表明在该群体中存在细胞自主性效应。MSN 特异性 PGC-1α 缺失导致先前鉴定的神经元和代谢 PGC-1α 依赖性基因减少，而不会导致纹状体空泡化。有趣的是，这些小鼠随着年龄的增长表现出活动减少，类似于几种 HD 动物模型。然而，这些新发现的 PGC-1α 依赖性基因在 knock-in HD 小鼠模型中随着疾病严重程度和年龄的增加而上调，而与 PGC-1α 转录的变化无关，这与功能丧失病因机制所预测的情况相反。这些数据表明，PGC-1α 是 MSN 转录本动态平衡和年龄相关功能所必需的，尽管 PGC-1α 在 MSNs 中的缺失不能复制类似 HD 的表型，但它的下游基因以重复长度和年龄依赖性的方式发生改变。了解 PGC-1α 基因功能变异和突变亨廷顿蛋白对该细胞类型转录的附加影响，可能为理解 HD 中 MSNs 的选择性易损性提供线索。
