Phospho-β-catenin accumulation in Alzheimer's disease and in aggresomes attributable to proteasome dysfunction
Phospho-β-catenin accumulation in Alzheimer's disease and in aggresomes attributable to proteasome dysfunction
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DOI：
10.1385/jmn:25:1:079
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发表时间：
2005-01-01
影响因子：
3.1
通讯作者：
Miller, CA
中科院分区：
文献类型：
--
作者：
Ghanevati, M;Miller, CA
在包括阿尔茨海默病（Alzheimer 'sdisease，AD）在内的许多神经退行性疾病中，胞浆内包涵体的积聚可能是由于泛素-蛋白酶体系统功能障碍所致。该系统降解许多细胞蛋白，包括β-连环蛋白，Wnt信号通路的成员，和早老素-1相互作用蛋白。β-连环蛋白的磷酸化标志着它的泛素化和快速的蛋白酶体降解。我们发现磷酸-β-连环蛋白积累的洗涤剂不溶性，点状，在海马锥体神经元胞质内含物比老年对照组更丰富。在AD中，β-连环蛋白与泛素结合，因此表明蛋白酶体依赖性降解受损。磷酸-β-连环蛋白部分隔离在颗粒空泡变性体内，但不在溶酶体中，表明隔离在自噬体内。将神经元培养物暴露于蛋白酶体抑制剂诱导形成洗涤剂不溶性的磷酸-β-连环蛋白阳性胞质内含物，其合并成侵袭体并与γ-微管蛋白和波形蛋白共定位。这些聚集物与凋亡性细胞死亡和半胱天冬酶-3，c-Jun-N-末端激酶，这些发现表明AD中磷酸-β-连环蛋白的积累可能是由于蛋白酶体功能受损。
Accumulation of cytoplasmic inclusion bodies in many neurodegenerative diseases, including Alzheimer's disease (AD), might result from dysfunction of the ubiquitin-proteasome system. This system degrades many cellular proteins, including beta-catenin, a member of the Wnt signaling pathway, and a presenilin-1-interacting protein. Phosphorylation of beta-catenin marks it for ubiquitination and rapid proteasomal degradation. We found phospho-beta-catenin accumulated as detergent-insoluble, punctate, cytoplasmic inclusions in hippocampal pyramidal neurons more abundantly in AD than in aged controls. In AD, beta-catenin was ubiquitin conjugated, thus suggesting impaired proteasome-dependent degradation. Phospho-beta-catenin was partially sequestered within granulovacuolar degeneration bodies but not in lysosomes, indicating sequestration within autophagosomes. Exposure of neuronal cultures to proteasome inhibitors induced formation of detergent-insoluble, phospho-beta-catenin-positive cytoplasmic inclusions that coalesced into aggresomes and colocalized with gamma-tubulin and vimentin These aggregates were associated with apoptotic cell death and with activation of caspase-3, c-Jun-N-terminal kinases, and c-Jun. These findings suggest that phospho-beta-catenin accumulation in AD might result from impaired proteasome function.