The role of Sirt1 in Huntington's Disease.

描述（由申请人提供）：Sirt1是一种nad依赖性蛋白去乙酰化酶，在哺乳动物细胞代谢状态和应激反应中已成为重要的转录调节因子。SIRT1在阿尔茨海默病、肌萎缩性侧索硬化症、亨廷顿舞蹈症和帕金森病模型中可以预防沃勒氏变性和神经变性。Sirt1在多种疾病模型中起保护作用的事实表明，Sirt1在正常和异常神经元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然未知。作为我们最初努力定义Sirt1在中枢神经系统中的生理功能的一部分，我们发现Sirt1使TORC1（受调节CREB活性的传感器）去乙酰化并激活CREB介导的转录。作为CREB的共激活因子，TORC1调节许多与神经退行性疾病发病机制有关的重要基因的转录，如pgc -1 α和BDNF。TORC1调节神经元活动依赖性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，因此它可能代表神经元Sirt1功能的独特靶点。然而，很可能Sirt1

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.