Inhibition of the ubiquitin-proteasome system in Alzheimer's disease
Inhibition of the ubiquitin-proteasome system in Alzheimer's disease
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DOI：
10.1073/pnas.170173897
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发表时间：
2000-08-29
影响因子：
11.1
通讯作者：
Layfield, R
中科院分区：
文献类型：
--
作者：
Lam, YA;Pickart, CM;Layfield, R
阿尔茨海默病是老年痴呆症最常见的原因。虽然在有家族病史的患者中发现了几种遗传缺陷，但大多数病例涉及没有已知遗传倾向的个体。泛素的突变形式，称为Ub（+1），已被选择性地观察到在阿尔茨海默氏症患者的大脑中，包括那些非家族性阿尔茨海默氏症，但一直不清楚为什么Ub（+1）表达应该是有害的。在这里，我们表明，Ub（+1）是一个有效的底物在体外和转染的人细胞中的多聚泛素化。所得到的多聚泛素链不易被去泛素化酶分解，并有效地抑制纯化的26 S蛋白酶体对多聚泛素化底物的降解。因此，Ub（+1）在衰老脑中的表达可导致Ub-蛋白酶体系统的显性抑制，从而导致神经病理学后果。
Alzheimer's disease is the most common cause of dementia in the elderly. Although several genetic defects have been identified in patients with a family history of this disease, the majority of cases involve individuals with no known genetic predisposition. A mutant form of ubiquitin, termed Ub(+1), has been selectively observed in the brains of Alzheimer's patients, including those with nonfamilial Alzheimer's disease, but it has been unclear why Ub(+1) expression should be deleterious. Here we show that Ub(+1) is an efficient substrate for polyubiquitination in vitro and in transfected human cells. The resulting polyubiquitin chains are refractory to disassembly by deubiquitinating enzymes and potently inhibit the degradation of a polyubiquitinated substrate by purified 26S proteasomes. Thus, expression of Ub(+1) in aging brain could result in dominant inhibition of the Ub-proteasome system, leading to neuropathologic consequences.