AMYLOID BETA-PROTEIN INHIBITS UBIQUITIN-DEPENDENT PROTEIN-DEGRADATION IN-VITRO
AMYLOID BETA-PROTEIN INHIBITS UBIQUITIN-DEPENDENT PROTEIN-DEGRADATION IN-VITRO
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DOI：
10.1074/jbc.270.34.19702
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发表时间：
1995-08-25
影响因子：
4.8
通讯作者：
GOLDGABER, D
中科院分区：
文献类型：
--
作者：
GREGORI, L;FUCHS, C;GOLDGABER, D
泛素结合物在包涵体和神经元缠结中的神经元内积累是神经退行性疾病（如阿尔茨海默病和唐氏综合征）和脑正常衰老的病理特征。淀粉样β蛋白（A β）及其前体存在于含有神经元缠结的神经元中。A β是细胞外斑块的主要成分，我们发现A β在体外作为泛素依赖性蛋白降解的抑制剂。我们研究了A β对这种蛋白水解途径步骤的影响，这些步骤有助于细胞中泛素缀合物的水平。A β的存在既不影响缀合物的形成，也不影响缀合物的去泛素化。然而，A β显著降低了结合物降解速率。我们的研究结果表明，A β与泛素降解途径的蛋白水解步骤相互作用，由于这一步骤是由26 S蛋白酶体完成的，因此确定了A β对该蛋白水解复合物的催化核心20 S蛋白酶体的影响，我们发现A β选择性地抑制20 S蛋白酶体的糜蛋白酶样活性。在病变神经元中，A β可通过抑制26 S蛋白酶体的活性来干扰泛素依赖的降解，这一发现可能解释了泛素结合物积累的起源。
Intraneuronal accumulation of ubiquitin conjugates in inclusion bodies and neurofibrillary tangles is a pathological feature of neurodegenerative disorders such as Alzheimer's disease and Down's syndrome and of normal aging of the brain, Amyloid beta-protein (A beta) and its precursor are found in neurofibrillary tangle-containing neurons. A beta is the major component of extracellular plaques, We showed that A beta acts as an inhibitor of the ubiquitin-dependent protein degradation in vitro. We examined the effect of A beta on the steps of this proteolytic pathway that contribute to the level of ubiquitin conjugates in the cell, Neither conjugate formation nor conjugate deubiquitination was affected by the presence of A beta. However, A beta significantly reduced the rate of conjugate degradation. Our results indicate that A beta interacts with the proteolytic step of the ubiquitin degradative pathway, Since this step is performed by the 26 S proteasome, the effect of A beta on the catalytic core of this proteolytic complex, the 20 S proteasome, was determined, We found that A beta selectively inhibits the chymotrypsin-like activity of the 20 S proteasome. Under pathological conditions in the affected neuron, A beta could interfere with ubiquitin-dependent degradation by inhibiting the 26 S proteasome activity, This finding may explain the origin of the accumulation of ubiquitin conjugates.