The role of Sirt1 in Huntington's Disease.

描述(申请人提供)：SIRT1，一种依赖NAD的蛋白质去乙酰基酶，已成为哺乳动物对细胞代谢状态和应激反应的重要转录调节因子。在阿尔茨海默病、肌萎缩侧索硬化症、亨廷顿病和帕金森病的模型中，SIRT1可以防止沃勒变性和神经退化。Sirt1在各种疾病模型中起保护作用的事实表明，Sirt1在正常和异常的神经功能中具有更普遍的功能。然而，Sirt1在神经元中的正常功能在很大程度上仍不清楚。作为我们最初为确定Sirt1在中枢神经系统中的生理功能所做的努力的一部分，我们发现SIRT1去乙酰化了TORC1(调节CREB活性的转导)并激活了CREB介导的转录。作为CREB的共激活因子，TORC1调控着许多重要基因的转录，这些基因参与了神经退行性疾病的发病机制，如PGC-1α和BDNF。TORC1调节神经元活性依赖的CREB转录，我们假设Sirt1在这一过程中发挥作用。由于TORC1仅在中枢神经系统和睾丸中表达，因此它可能是神经元Sirt1功能的独特靶点。然而，很可能Sirt1 调节神经元中的其他靶点，特别是考虑到超过40个靶点 SIRT1已在非神经系统中被发现。我们发现突变的Huntingtin对Sirt1脱乙酰基酶的活性有抑制作用。这种抑制可能导致HD脑中Sirt1的许多靶点的解除调控。我们建议研究Sirt1及其靶点在正常神经元和HD神经元中的作用。在Sirt1存在或不存在的情况下，原代神经元中神经元活性依赖的调节基因的表达将被评估。依赖于TORC1的表达谱将与Sirt1谱相比较。我们还将研究更高水平的Sirt1过度表达是否能在类HD小鼠中提供剂量依赖性的神经保护。对HD发病机制中的Sirt1靶点进行无偏和有偏研究。更广泛地说，这项工作将加深我们对sirtuins和健康大脑老化之间确切机制联系的理解，并加强延缓和改善神经退行性疾病的药物的开发。

DESCRIPTION (provided by applicant): Sirt1, an NAD-dependent protein deacetylase has emerged as important regulator of mammalian transcription in response to cellular metabolic status and stress. SIRT1 protects from Wallerian degeneration and protects against neurodegeneration in models of Alzheimer's disease, Amyotrophic lateral sclerosis, Huntington's and Parkinson's disease. The fact that Sirt1 protects in various disease models suggests a more general function of Sirt1 in normal and abnormal neuronal function. However, normal function of Sirt1 in neurons remains largely unknown. As part of our initial effort to defin the physiological function of Sirt1 in CNS, we found that SIRT1 deacetylates TORC1 (Transducer of Regulated CREB activity) and activates CREB mediated transcription. As coactivator of CREB, TORC1 regulates transcription of a number of important genes that have been implicated in the pathogenesis of neurodegenerative disorders, such as PGC-1alpha and BDNF. TORC1 regulates neuronal activity-dependent CREB transcription and we hypothesize that Sirt1 plays a role in this process. Since TORC1 is only expressed in CNS and testis, it potentially represents a unique target of neuronal Sirt1 function. However, it is likely that Sirt1 regulates other targets in neurons, especially in light of the fact that more than forty targets of Sirt1 have been identified in non-neuronal systems. We found that Sirt1 deactylase activity was inhibited by mutant huntingtin. This inhibition presumably leads to deregulation of numerous targets of Sirt1 in HD brain. We propose to examine the role of Sirt1 and its targets in normal and HD neurons. Neuronal activity-dependent regulation gene expression will be assessed in primary neurons in the presence or absence of Sirt1. TORC1-dependent expression profiles will be compared with Sirt1 profiles. We will also examine if higher levels of Sirt1 overexpression afford dose-dependent neuroprotection in HD-like mice. Unbiased and biased studies will be performed to examine Sirt1 targets in HD pathogenesis. More generally, this work will further our understanding of the precise mechanistic link between the sirtuins and healthy brain aging, and potentiate development of drugs that delay and ameliorate neurodegenerative diseases.