Desrosiers Richard R, Fanélus Irvens
Université du Québec à Montréal, C.P. 8888, Succursale Centre-Ville, Montréal, Québec, Canada, H3C 3P8.
Curr Aging Sci. 2011 Feb;4(1):8-18.
Proteins are susceptible to numerous non-enzymatic post-translational modifications which occur both during normal aging and in neurodegenerative states. For instance, formation of abnormal L-isoaspartyl residues arising from both the deamidation of L-asparaginyl residues and the isomerization of L-aspartyl residues is a frequent chemical modification that affects proteins. The formation of L- isoaspartyl residues in proteins alters their three-dimensional structure leading usually to a loss of function. Notably, accumulation of isomerized proteins could contribute to metabolic dysfunctions in neuronal cells during aging reducing cognitive functions in elderly patients and would eventually promote the development of neurodegenerative diseases. The protein L-isoaspartyl (D-aspartyl) methyltransferase (PIMT) is an enzyme that recognizes and repairs the abnormal L-isoaspartyl residues in proteins. Its expression appears to decline during aging which could partially explain the build up of damaged proteins in old age. In this review, we summarize recent findings, based mostly on proteomic data, regarding the formation and accumulation of proteins bearing atypical L-isoaspartyl residues as well as PIMT functions during normal aging and in some neurodegenerative diseases. The emphasis is on possible molecular mechanisms controlling PIMT expression and the ability of PIMT to repair isomerized substrates during aging. Investigation of processes regulating age-related accumulation of isomerized proteins is a promising avenue to a better understanding of aging at the protein level.
蛋白质易受多种非酶促翻译后修饰的影响，这些修饰在正常衰老过程和神经退行性病变状态下均会发生。例如，由L-天冬酰胺残基脱酰胺和L-天冬氨酸残基异构化产生的异常L-异天冬氨酸残基的形成是一种常见的影响蛋白质的化学修饰。蛋白质中L-异天冬氨酸残基的形成会改变其三维结构，通常导致功能丧失。值得注意的是，异构化蛋白质的积累可能导致衰老过程中神经元细胞的代谢功能障碍，降低老年患者的认知功能，并最终促进神经退行性疾病的发展。蛋白质L-异天冬氨酸（D-天冬氨酸）甲基转移酶（PIMT）是一种识别并修复蛋白质中异常L-异天冬氨酸残基的酶。其表达在衰老过程中似乎会下降，这可能部分解释了老年时受损蛋白质的积累。在本综述中，我们主要基于蛋白质组学数据，总结了关于带有非典型L-异天冬氨酸残基的蛋白质的形成和积累以及正常衰老和某些神经退行性疾病中PIMT功能的最新发现。重点是控制PIMT表达的可能分子机制以及衰老过程中PIMT修复异构化底物的能力。研究调节与年龄相关的异构化蛋白质积累的过程是在蛋白质水平上更好地理解衰老的一个有前景的途径。
