α-synuclein alters proteasome function, protein synthesis, and stationary phase viability
α-synuclein alters proteasome function, protein synthesis, and stationary phase viability
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DOI：
10.1074/jbc.m501308200
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发表时间：
2005-08-26
影响因子：
4.8
通讯作者：
Keller, JN
中科院分区：
文献类型：
--
作者：
Chen, QH;Thorpe, J;Keller, JN
α-突触核蛋白似乎在许多神经变性疾病（统称为突触核蛋白病）中在介导神经毒性中起作用。这些疾病中的大多数与衰老和蛋白酶体-蛋白水解途径的可能损伤有关，尽管衰老、蛋白酶体抑制和α-突触核蛋白毒性之间的关系尚未完全阐明。最近的研究表明，酵母可能提供了一个有用的系统，用于研究有丝分裂细胞中α-突触核蛋白的生物学和毒性，概括了在各种突触核蛋白病疾病中观察到的许多特征。进一步的研究表明，酵母老化的稳定期模型为理解有丝分裂后细胞老化的生物化学和调控提供了一个有用的系统。在本研究中，我们研究了野生型和突变型α-突触核蛋白（A30 P）对蛋白酶体稳态，蛋白质合成以及细胞在稳定期老化中存活的能力的多个方面的影响。这些数据表明，α-突触核蛋白改变蛋白酶体组成，损害蛋白酶体介导的蛋白质降解，损害蛋白质合成，并损害细胞承受稳定期老化的能力。有趣的是，α-突触核蛋白对细胞内蛋白酶体含量或蛋白质泛素化几乎没有影响，并且不会增加细胞对各种应激源的脆弱性。总之，这些数据表明，酵母可能是有用的理解能力的α-突触核蛋白损害蛋白酶体介导的蛋白质降解，以及了解的基础上与年龄相关的α-突触核蛋白的细胞毒性。
alpha-Synuclein appears to play a role in mediating neurotoxicity in a number of neurodegenerative disorders, collectively referred to as synucleinopathies. Most of these disorders are associated with aging and a probable impairment of the proteasome-proteolytic pathway, although the relationship between aging, proteasome inhibition, and alpha-synuclein toxicity has not been fully elucidated. Recent studies suggest that yeast may provide a useful system for studying the biology and toxicity of alpha-synuclein in mitotic cells, recapitulating many features observed in the various synucleinopathy disorders. Additional studies indicate that the stationary phase model of aging in yeast provides a useful system for understanding the biochemistry and regulation of aging in post-mitotic cells. In the present study we examined the effect of wild type and mutant alpha-synuclein (A30P) on multiple aspects of proteasome homeostasis, protein synthesis, as well as the ability of cells to survive stationary phase aging. These data demonstrate that alpha-synuclein alters proteasome composition, impairs proteasome-mediated protein degradation, impairs protein synthesis, and impairs the ability of cells to withstand stationary phase aging. Interestingly, alpha-synuclein had little effect on intracellular proteasome content or protein ubiquitination, and did not increase the vulnerability of cells to a variety of stressors. Together, these data suggest that yeast may be useful for understanding the ability of alpha-synuclein to impair proteasome-mediated protein degradation, as well as for understanding the basis for age-related alpha-synuclein cytotoxicity.