An investigation into chronic implanted subgaleal electroencephalography for neurophysiological biomarker tracking in movement disorders

项目摘要/摘要 蛋白质质量控制的扰动与许多与年龄相关的神经退行性疾病有关， 其典型的特征是聚集的蛋白质，如α-突触核蛋白。近期 研究表明，泛素依赖的蛋白质质量控制蛋白泛素-2(UBQLN2)是共定位的 在阿尔茨海默病和相关痴呆(ADRD)的主要原因中存在蛋白质聚集体，包括路易 躯体痴呆症和帕金森氏症等。UBQLN2与疾病的相互作用 聚集体暗示UBQLN2是这些疾病的一个潜在因素。UBQLN2含有N-末端泛素- 类似(UBL)和C端泛素相关(UBA)结构域，允许UBQLN2穿梭泛素化 底物到蛋白酶体以供降解。UBQLN2也可能以自噬降解的蛋白质为靶标， 尽管这在文献中并没有得到很好的证实。这项建议将建立在最近的模型和试剂的基础上 我们实验室开发的目的是探索UBQLN2在共核疾病中的作用。多项研究表明 在疾病中，UBQLN2与a-突触核蛋白聚合体共定位，但尚不清楚UBQLN2是否正常 在处理α-突触核蛋白或其他支持ADRD的显著蛋白质方面发挥作用。初步研究表明 结果表明，UBQLN2过表达显著减少 A-突触核蛋白水平，而UBQLN2基因敲除增加 A-突触核蛋白水平。该提案将界定UBQLN2在清算中的作用 A-突触核蛋白，无论是正常还是在 疾病状态。为了实现这一目标，我将使用鼠标模型来研究UBQLN2在清除过程中的作用 并确定UBQLN2介导的清除是否改善了a-突触核蛋白的病理变化。我也会 使用细胞模型研究UBQLN2调节α-突触核蛋白的机制，利用 结构域缺失突变体研究泛素、伴侣和蛋白酶体结合结构域在 UBQLN在介导α-突触核蛋白清除中的作用。拟议的研究将有助于更好地了解 蛋白质质量控制通路在神经退行性疾病中的作用并可能揭示新的治疗方法 老年性痴呆症的目标。这项工作也将是我继续攻读研究生和博士后的基础 在我准备成为一名独立科学家的职业生涯时，我接受了培训。

PROJECT SUMMARY/ABSTRACT Perturbations in protein quality control have been implicated in many age-related neurodegenerative diseases, which are typically characterized by the accumulation of aggregated proteins such as a-synuclein. Recent studies have shown that ubiquilin-2 (UBQLN2), a ubiquitin-dependent protein quality control protein, co-localizes with protein aggregates in major causes of Alzheimer’s disease and related dementias (ADRD), including Lewy body dementia and Parkinson’s disease, among others. The interaction between UBQLN2 and disease aggregates implicates UBQLN2 as a potential factor in these disorders. UBQLN2 contains N-terminal ubiquitin- like (UBL) and C-terminal ubiquitin-associated (UBA) domains that allow UBQLN2 to shuttle ubiquitinated substrates to the proteasome for degradation. UBQLN2 may also target proteins for degradation by autophagy, although this is not as well established in the literature. This proposal will build on recent models and reagents developed in our laboratory to explore the role of UBQLN2 in synucleinopathies. Several studies have shown that UBQLN2 co-localizes with a-synuclein aggregates in disease, but it is unknown whether UBQLN2 normally plays a role in handling a-synuclein or the other prominent proteins underlying ADRD. Preliminary studies have shown that UBQLN2 overexpression markedly reduces a-synuclein levels, while UBQLN2 knockdown increases a-synuclein levels. This proposal will define the role of UBQLN2 in clearing a-synuclein, both normally and in disease states. To accomplish this goal, I will use mouse models to investigate the role of UBQLN2 in clearing a-synuclein in vivo and determine if UBQLN2-mediated clearance ameliorates a-synuclein pathology. I will also use cellular models to investigate the mechanism by which UBQLN2 regulates a-synuclein, making use of domain deletion mutants to investigate the role of ubiquitin, chaperone, and proteasome binding domains on UBQLN2 in mediating the clearance of a-synuclein. The proposed studies will lead to a better understanding of the role of protein quality control pathways in neurodegenerative disease and may reveal novel therapeutic targets for age-related dementias. This work will also be foundational to my continued graduate and postdoctoral training as I prepare for a career as an independent scientist.