Shimizu T, Watanabe A, Ogawara M, Mori H, Shirasawa T
Department of Molecular Genetics, Tokyo Metropolitan Institute of Gerontology, Japan.
Arch Biochem Biophys. 2000 Sep 15;381(2):225-34. doi: 10.1006/abbi.2000.1955.
We reviewed here that protein isomerization is enhanced in amyloid-beta peptides (Abeta) and paired helical filaments (PHFs) purified from Alzheimer's disease (AD) brains. Biochemical analyses revealed that Abeta purified from senile plaques and vascular amyloid are isomerized at Asp-1 and Asp-7. A specific antibody recognizing isoAsp-23 of Abeta further suggested the isomerization of Abeta at Asp-23 in vascular amyloid as well as in the core of senile plaques. Biochemical analyses of purified PHFs also revealed that heterogeneous molecular weight tau contains L-isoaspartate at Asp-193, Asn-381, and Asp-387, indicating a modification, other than phosphorylation, that differentiates between normal tau and PHF tau. Since protein isomerization as L-isoaspartate causes structural changes and functional inactivation, or enhances the aggregation process, this modification is proposed as one of the progression factors in AD. Protein L-isoaspartyl methyltransferase (PIMT) is suggested to play a role in the repair of isomerized proteins containing L-isoaspartate. We show here that PIMT is upregulated in neurodegenerative neurons and colocalizes in neurofibrillary tangles (NFTs) in AD. Taken together with the enhanced protein isomerization in AD brains, it is implicated that the upregulated PIMT may associate with increased protein isomerization in AD. We also reviewed studies on PIMT-deficient mice that confirmed that PIMT plays a physiological role in the repair of isomerized proteins containing L-isoaspartate. The knockout study also suggested that the brain of PIMT-deficient mice manifested neurodegenerative changes concomitant with accumulation of L-isoaspartate. We discuss the pathological implications of protein isomerization in the neurodegeneration found in model mice and AD.
我们在此回顾，从阿尔茨海默病（AD）大脑中纯化出的淀粉样β肽（Aβ）和双螺旋丝（PHF）中，蛋白质异构化增强。生化分析显示，从老年斑和血管淀粉样蛋白中纯化出的Aβ在天冬氨酸-1和天冬氨酸-7处发生异构化。一种识别Aβ异天冬氨酸-23的特异性抗体进一步表明，血管淀粉样蛋白以及老年斑核心中的Aβ在天冬氨酸-23处发生异构化。对纯化的PHF进行生化分析还显示，分子量不均一的tau蛋白在天冬氨酸-193、天冬酰胺-381和天冬氨酸-387处含有L-异天冬氨酸，这表明除磷酸化外，还有一种修饰可区分正常tau蛋白和PHF tau蛋白。由于L-异天冬氨酸形式的蛋白质异构化会导致结构变化和功能失活，或增强聚集过程，因此这种修饰被认为是AD进展的因素之一。蛋白质L-异天冬氨酰甲基转移酶（PIMT）被认为在修复含有L-异天冬氨酸的异构化蛋白质中起作用。我们在此表明，PIMT在神经退行性神经元中上调，并在AD的神经原纤维缠结（NFT）中共定位。结合AD大脑中增强的蛋白质异构化，提示上调的PIMT可能与AD中蛋白质异构化增加有关。我们还回顾了关于PIMT缺陷小鼠的研究，这些研究证实PIMT在修复含有L-异天冬氨酸的异构化蛋白质中起生理作用。基因敲除研究还表明，PIMT缺陷小鼠的大脑表现出神经退行性变化，并伴有L-异天冬氨酸的积累。我们讨论了蛋白质异构化在模型小鼠和AD中发现的神经退行性变中的病理意义。
