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

描述（由申请人提供）：本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，以便将其用于神经退行性疾病（如脊髓延髓肌萎缩症（SBMA））的治疗干预。SBMA是一种遗传性疾病，其特征是脑干和脊髓中运动神经元的进行性丧失。SBMA是由雄激素受体基因第一外显子中的三核苷酸（CAG）重复扩增引起的，导致AR蛋白中的多聚谷氨酰胺扩增。与其他多聚谷氨酰胺疾病一样，SBMA的特征是在退化的神经元中错误折叠的蛋白质聚集体的积累。组蛋白去乙酰化酶6（HDAC 6）是一种微管相关的去乙酰化酶，具有内在的多聚泛素结合活性。我们最近确定HDAC 6的过表达挽救了SBMA果蝇、蛋白酶体突变果蝇和其他神经退行性疾病果蝇模型的变性。HDAC 6通过促进自噬-溶酶体系统降解异常的泛素化蛋白质来挽救变性。在本申请中，我们将（1）测试关于HDAC 6促进异常蛋白自噬降解的分子机制的特定假设，（2）确定HDAC 6在哺乳动物中的治疗潜力，以及（3）使用苍蝇遗传学的力量来获得对HDAC 6在错误折叠蛋白应激的细胞管理中的作用的意外见解。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HDAC 6的功能。本申请试图了解HDAC 6功能的机制，以便其可用于治疗开发。

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.