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Characterizing the role of the polyglutamine neurodegenerative protein ataxin-3 in the ubiquitin-proteasome pathway.

机译：表征多谷氨酰胺神经退行性蛋白共济失调蛋白3在泛素-蛋白酶体途径中的作用。

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摘要

Spinocerebellar ataxia type 3/Machado Joseph disease is a dominantly inherited neurodegenerative disease caused by expansion of a polyglutamine domain in the protein ataxin-3 (AT3). In normal individuals the gene contains 12--40 CAG repeats expanding to 55--86 repeats in clinically diagnosed MJD patients. Expansion of the glutamine domain in AT3 as well as in at least 8 other members of the polyglutamine neurodegenerative disease family increases protein misfolding resulting in aggregation and formation of nuclear inclusions. At the start of this thesis the normal physiological function of AT3 was unknown. A bioinformatic study revealed that AT3 contained multiple ubiquitin interacting motifs (UIMs) providing a potential link between AT3 and the ubiquitin-proteasome pathway. The objective of my thesis was to determine if AT3 UIMs were functional and then determine if AT3 had a role in the ubiquitin-proteasome pathway. Studies presented in this thesis show that AT3 is a deubiquitylating enzyme that may be involved in protein quality control. AT3 has several properties characteristic of deubiquitylating enzymes including removing ubiquitin from polyubiquitin chains, on 125I-lysozyme, and cellular proteins, cleaving a ubiquitin protease substrate, and binding the specific ubiquitin protease inhibitor, ubiquitin-aldehyde. Mutating the predicted catalytic cysteine in AT3 inhibits each of these ubiquitin protease activities. The ability to bind and cleave ubiquitylated proteins is consistent with AT3 playing a role in the ubiquitin-proteasome system. Cellular studies show that endogenous AT3 co-localizes with aggresomes and preaggresome particles of misfolded cystic fibrosis transmembrane regulator mutant, CFTRDeltaF508, and associates with histone deacetylase 6 (HDAC6) and dynein, proteins required for aggresome formation and transport of misfolded protein. SiRNA knockdown of AT3 greatly reduces aggresomes formed by CFTRDeltaF508 demonstrating a critical role of AT3 in this process. These and other data indicate that both the deubiquitylating activity of AT3 as well as its UIMs play essential roles in CFTRDeltaF508 aggresome formation and raises the possibility that pathological AT3, which tends to misfold and aggregate, may be exposed to aggregate-prone misfolded/denatured proteins as part of its normal function.
机译：脊髓小脑性共济失调3型/马查多·约瑟夫病是一种主要遗传的神经退行性疾病，是由蛋白ataxin-3（AT3）中的聚谷氨酰胺结构域扩展引起的。在正常个体中，该基因包含12--40个CAG重复序列，在临床诊断的MJD患者中扩展为55--86个重复序列。 AT3以及至少8个其他聚谷氨酰胺神经退行性疾病家族成员中的谷氨酰胺结构域的扩增会增加蛋白质错折叠，导致聚集和核内含物的形成。在本文开始时，AT3的正常生理功能尚不清楚。一项生物信息学研究表明，AT3包含多个泛素相互作用基序（UIM），从而提供AT3与泛素-蛋白酶体途径之间的潜在联系。本文的目的是确定AT3 UIM是否起作用，然后确定AT3是否在泛素-蛋白酶体途径中起作用。本文提出的研究表明，AT3是一种去泛素化酶，可能参与蛋白质质量控​​制。 AT3具有去泛素化酶的几种特性，包括从125I溶菌酶和细胞蛋白上的多泛素链上去除泛素，裂解泛素蛋白酶底物，并结合特定的泛素蛋白酶抑制剂泛素-醛。在AT3中突变预测的催化半胱氨酸会抑制这些泛素蛋白酶的每一种活性。结合和切割泛素化蛋白的能力与AT3在泛素-蛋白酶体系统中发挥作用相一致。细胞研究表明，内源性AT3与错误折叠的囊性纤维化跨膜调节突变体CFTRDeltaF508的聚集体和预聚集颗粒共定位，并与组蛋白脱乙酰基酶6（HDAC6）和dynein结合，这是聚集体形成和错误折叠的蛋白质运输所必需的蛋白质。敲除AT3的SiRNA大大减少了CFTRDeltaF508形成的聚集体，证明了AT3在此过程中的关键作用。这些和其他数据表明，AT3的去泛素化活性及其UIM在CFTRDeltaF508集聚体形成中起着重要作用，并增加了可能会错折叠和聚集的病理性AT3可能暴露于易于聚集的错折叠/变性蛋白质的可能性。作为其正常功能的一部分。

著录项

  • 作者

    Burnett, Barrington.;

  • 作者单位

    University of Pennsylvania.;

  • 授予单位 University of Pennsylvania.;
  • 学科 Health Sciences Pharmacology.; Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2005
  • 页码 170 p.
  • 总页数 170
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 药理学;神经科学;
  • 关键词

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