Modulation of the PPAR-delta Signaling Pathway in Huntingtons Disease

描述（由申请人提供）：亨廷顿氏病（HD）是一种持续进展的常染色体显性神经退行性疾病，其特征是不自主运动、认知能力下降和精神疾病(1)。这种多聚谷氨酰胺疾病是由编码扩展多聚谷氨酰胺（polyQ）通道的亨廷顿蛋白（Htt）基因编码区CAG三核苷酸重复扩增突变引起的。我们实验室和其他人最近的研究表明，HD患者的线粒体功能障碍和代谢缺陷是由于过氧化物酶体增殖体激活受体γ共激活因子-1 α （PGC- 1¿）转录失调所致（2,3）。作为一种转录调节剂，PGC-1可以正向调节几种核受体转录因子，包括三种过氧化物酶体增殖物激活受体（PPAR）亚型。，和¿？其中，PPAR¿是中枢神经系统（CNS）中表达最丰富的亚型，尽管其在该组织中的功能相关性尚未得到很好的定义（4,5）。随着维甲酸与PPAR¿结合介导其先前充分记录的促生存作用的发现（6,7），PPAR¿可能负责促进神经元中的各种生存/修复过程（8-10）。PPAR信号转录途径的多个组成部分已经在非神经元系统中被阐明（6,7）。药理学（26）和遗传学（27,28）的PPAR激活增加了参与能量代谢和线粒体生物发生的基因的表达。PPAR¿在神经元功能中的作用尚未明确，尽管其表达水平高于肌肉（29）。在Aim 1中，我将检验聚谷氨酰胺扩展的亨廷顿蛋白干扰PPAR介导的基因转录的假设，这种干扰可能有助于亨廷顿病的分子病理学。在目标2中，我将进行体外和体内实验，以验证增强PPAR信号通路将改善HD中出现的转录功能障碍和神经元变性的假设。通过阐明PPAR信号通路在HD中的作用，不仅可以找到HD的治疗靶点，还可以找到其他多聚谷氨酰胺疾病和神经退行性疾病的治疗靶点。

DESCRIPTION (provided by applicant): Huntington's disease (HD) is a relentlessly progressive autosomal dominant neurodegenerative disorder characterized by the development of involuntary movements, cognitive decline, and psychiatric illness (1). This polyglutamine disorder arises from a CAG trinucleotide-repeat expansion mutation in the coding region of the huntingtin (Htt) gene encoding an extended polyglutamine (polyQ) tract. Recent studies by our laboratory and others have shown that the mitochondrial dysfunction and metabolic deficits in HD result from transcriptional dysregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC- 1¿) (2, 3). As a transcriptional regulator, PGC-1¿ positively modulates several nuclear receptor transcription factors including the three Peroxisome Proliferator-Activated Receptor (PPAR) isoforms, ¿, ?, and ¿. Of these, PPAR ¿ is the most abundantly expressed subtype in the central nervous system (CNS), although its functional relevance in this tissue has not been well defined (4, 5). With the discovery that retinoic acid binds to PPAR ¿ to mediate its previously well-documented pro-survival effects (6, 7), PPAR ¿ may be responsible for promoting a variety of survival / repair processes in neurons (8-10). Multiple components of the PPAR ¿ signaling transcriptional pathway have been elucidated in non-neuronal systems (6, 7). Pharmacologic (26) and genetic (27,28) activation of PPAR¿ increases expression of genes involved in energy metabolism and mitochondrial biogenesis. The role of PPAR ¿ in neuronal function has not been well-defined, despite being expressed at levels higher than those in muscle (29). In Aim 1, I will test the hypothesis that polyglutamine-expanded huntingtin protein interferes with PPAR ¿ -mediated gene transcription, a perturbation that may contribute to the molecular pathology of Huntington's disease. In Aim 2, I will perform experiments in vitro and in vivo to test the hypothesis that enhancing the PPAR ¿ signaling pathway will ameliorate transcriptional dysfunction and neuronal degeneration seen in HD. By elucidating the role of the PPAR ¿ signaling pathway in HD, targets for treatment may be found not only for HD, but other polyglutamine diseases and neurodegenerative diseases. PUBLIC HEALTH RELEVANCE: Transcription dysregulation and mitochondrial dysfunction have been individually linked to the development of multiple human diseases, including neurodegenerative diseases. This investigation will elucidate mechanisms of transcriptional dysregulation that underlie mitochondrial dysfunction to potentially facilitate design of therapeutic strategies to treat Huntington's Disease, and possibly other polyglutamine disorders and other neurodegenerative disorders, such as Parkinson's Disease. !