HDAC6 and the intersection between the UPS, autophagy, and neurodegeneration

描述（由申请人提供）：该项目的长期目标是表征负责消除错误折叠的神经毒性蛋白质的分子机制，以便它们可能被用于神经退行性疾病的治疗干预，如脊髓球性肌萎缩症（SBMA）。SBMA是一种以脑干和脊髓运动神经元进行性丧失为特征的遗传性疾病。SBMA是由雄激素受体基因第一外显子的三核苷酸（CAG）重复扩增导致AR蛋白中的聚谷氨酰胺扩增引起的。与其他多聚谷氨酰胺疾病一样，SBMA的特征是变性神经元中错误折叠蛋白聚集体的积累。组蛋白去乙酰化酶6 （HDAC6）是一种微管相关的去乙酰化酶，具有内在的多泛素结合活性。我们最近发现，在SBMA果蝇、蛋白酶体突变果蝇和其他神经退行性疾病的果蝇模型中，HDAC6的过表达可以挽救退化。HDAC6通过促进自噬-溶酶体系统对异常泛素化蛋白的降解来挽救退化。在这个应用中，我们将(1)测试关于HDAC6促进异常蛋白自噬降解的分子机制的特定假设，(2)确定HDAC6在哺乳动物中的治疗潜力，(3)利用果蝇遗传学的力量获得HDAC6在错误折叠蛋白应激的细胞管理中的意想不到的作用。公共卫生相关性：组蛋白去乙酰化酶6有助于消除神经元中错误折叠的蛋白质，并防止神经变性。目前尚不清楚HDAC6的功能。这项应用旨在了解HDAC6功能的机制，以便它可能被用于治疗开发。

DESCRIPTION (provided by applicant): The long-term objective of this project is to characterize the molecular machinery responsible for eliminating misfolded, neurotoxic proteins so that they may be exploited for therapeutic intervention for neurodegenerative diseases such as spinobulbar muscular atrophy (SBMA). SBMA is a hereditary disease characterized by progressive loss of motor neurons in the brainstem and spinal cord. SBMA is caused by trinucleotide (CAG) repeat expansion in the first exon of the androgen receptor gene leading to polyglutamine expansion in AR protein. Like other polyglutamine diseases, SBMA is characterized by accumulation of misfolded protein aggregates in degenerating neurons. Histone deacetylase 6 (HDAC6) is a microtubule-associated deacetylase with intrinsic polyubiquitin-binding activity. We recently determined that over-expression of HDAC6 rescues degeneration in SBMA flies, flies with proteasome mutations, and other fly models of neurodegenerative disease. HDAC6 rescues degeneration by facilitating the degradation of aberrant, ubiquitinated protein by the autophagy-lysosomal system. In this application, we will (1) test specific hypotheses regarding the molecular mechanism whereby HDAC6 facilitates autophagic degradation of aberrant protein, (2) determine the therapeutic potential of HDAC6 in mammals, and (3) use the power of fly genetics to gain unanticipated insights into the role of HDAC6 in cellular management of misfolded protein stress. PUBLIC HEALTH RELEVANCE: Histone deacetylase 6 contributes to elimination of misfolded proteins from neurons and protects against neurodegeneration. It is not known how HDAC6 functions. This application seeks to understand the mechanism of HDAC6 function so that it may be exploited for therapeutics development.