加拿大研究人员22日说，大脑中一种关键蛋白质的变化可能是导致早老性痴呆症的主要原因，这一发现为早期诊断和治疗早老性痴呆症带来新希望。

加拿大麦基尔大学的希曼特·鲍德尔等人对一种在早老性痴呆症中起重要作用的TAU蛋白质进行了研究。在早老性痴呆症患者脑中，

这种蛋白质数量会无限制增加，并纠结在一起。此前研究表明，正常TAU蛋白质仅吸附3到4个磷酸盐，而早老性痴呆症患者的不正常TAU蛋白质能吸附21到25个磷酸盐。

鲍德尔等人通过研究FTDP-17遗传病来排除与早老性痴呆症无关的磷酸盐。FTDP-17遗传病是由TAU蛋白质变异引起的，其症状与早老性痴呆症非常相似。

他们发现，TAU蛋白质中有一种叫Ser202的氨基酸，只要有单个磷酸盐黏附到这种氨基酸上，就会导致TAU蛋白质不正常，进而诱发FTDP-17遗传病和早老性痴呆症。TAU蛋白质Ser202氨基酸吸附单个磷酸盐正是导致早老性痴呆症的“罪魁祸首”。

研究人员指出，这一发现使科学家的研究有了“明确方向”，在此基础上可开发出早期诊断早老性痴呆症的方法，甚至有关治疗药物。

这项研究成果已发表在美国《生物化学杂志》上。

推荐原始出处：

J. Biol. Chem., Vol. 284, Issue 20, 13422-13433, May 15, 2009

Familial FTDP-17 Missense Mutations Inhibit Microtubule Assembly-promoting Activity of Tau by Increasing Phosphorylation at Ser202 in Vitro*

Dong Han1, Hamid Y. Qureshi2, Yifan Lu, and Hemant K. Paudel3

From the  Bloomfield Center for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, and the Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H3T 1E2, Canada

In Alzheimer disease (AD), frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and other tauopathies, tau accumulates and forms paired helical filaments (PHFs) in the brain. Tau isolated from PHFs is phosphorylated at a number of sites, migrates as 60-, 64-, and 68-kDa bands on SDS-gel, and does not promote microtubule assembly. Upon dephosphorylation, the PHF-tau migrates as 50–60-kDa bands on SDS-gels in a manner similar to tau that is isolated from normal brain and promotes microtubule assembly. The site(s) that inhibits microtubule assembly-promoting activity when phosphorylated in the diseased brain is not known. In this study, when tau was phosphorylated by Cdk5 in vitro, its mobility shifted from 60-kDa bands to 64- and 68-kDa bands in a time-dependent manner. This mobility shift correlated with phosphorylation at Ser202, and Ser202 phosphorylation inhibited tau microtubule-assembly promoting activity. When several tau point mutants were analyzed, G272V, P301L, V337M, and R406W mutations associated with FTDP-17, but not nonspecific mutations S214A and S262A, promoted Ser202 phosphorylation and mobility shift to a 68-kDa band. Furthermore, Ser202 phosphorylation inhibited the microtubule assembly-promoting activity of FTDP-17 mutants more than of WT. Our data indicate that FTDP-17 missense mutations, by promoting phosphorylation at Ser202, inhibit the microtubule assembly-promoting activity of tau in vitro, suggesting that Ser202 phosphorylation plays a major role in the development of NFT pathology in AD and related tauopathies.