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描述负责消除错误折叠的神经毒性蛋白质的分子机制，以便将它们用于治疗神经退行性疾病，如脊髓延髓肌肉萎缩症(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上的三核苷酸(CAG)重复扩增导致AR蛋白中多谷氨酰胺的扩增引起的。与其他聚谷氨酰胺疾病一样，SBMA的特征是在退化的神经元中积累错误折叠的蛋白质聚集体。组蛋白脱乙酰酶6(HDAC6)是一种具有内源性多泛素结合活性的微管相关脱乙酰酶。我们最近确定，HDAC6的过度表达可以挽救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退变。HDAC6通过促进自噬-溶酶体系统对异常的泛素化蛋白的降解来挽救退化。在这一应用中，我们将(1)测试关于HDAC6促进异常蛋白质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，以及(3)利用果蝇遗传学的力量来获得对HDAC6在错误折叠蛋白质应激的细胞管理中的作用的意想不到的见解。与公共健康相关：组蛋白脱乙酰酶6有助于消除神经元中错误折叠的蛋白质，并防止神经退化。目前尚不清楚HDAC6的工作原理。本申请旨在了解HDAC6的作用机制，以便将其用于治疗学的开发。

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.