Proteasome inhibition and aggresome formation in sporadic inclusion-body myositis and in amyloid-β precursor protein-overexpressing cultured human muscle fibers
Proteasome inhibition and aggresome formation in sporadic inclusion-body myositis and in amyloid-β precursor protein-overexpressing cultured human muscle fibers
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DOI：
10.1016/s0002-9440(10)62994-x
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发表时间：
2005-08-01
影响因子：
6
通讯作者：
Askanas, V
中科院分区：
文献类型：
--
作者：
Fratta, P;Engel, WK;Askanas, V
26S蛋白酶体系统参与消除各种蛋白质，包括泛素化的错误折叠/未折叠蛋白质，其抑制导致蛋白质聚集体的细胞积累。肌纤维内泛素化多蛋白聚集是散发性包涵体肌炎（s-IBM）肌纤维的特征。存在两种主要类型的聚集体，包含淀粉样蛋白（A β）或磷酸化tau （p-tau）。我们现在想知道26S蛋白酶体的异常是否有助于s-IBM的发病机制，以及多蛋白聚集体是否具有聚集体的特征。我们还利用培养的人肌纤维研究了淀粉样蛋白- β前体蛋白（A β PP）过表达对蛋白酶体功能的影响以及蛋白酶体抑制对聚合体形成的影响。我们报道，在s-IBM肌肉活检中，在γ -微管蛋白相关的聚合体中免疫检测到26S蛋白酶体亚基，该聚合体也含有A β， p-tau，泛素和HSP70。此外，a)蛋白酶体亚基的表达量大幅增加，b) 20S α蛋白酶体亚基与a β PP/ a β共免疫沉淀，c)三大原体蛋白水解活性降低。在培养的肌纤维中，A β - pp过表达的纤维显示蛋白酶体蛋白水解活性降低，蛋白酶体抑制剂的添加显著增加了聚合体的形成。因此，s-IBM肌纤维的蛋白酶体功能障碍可能在错误折叠的积累中发挥作用，潜在的细胞毒性蛋白，并可能由细胞内a β PP/ a β增加诱导。
The 26S proteasome system is involved in eliminating various proteins, including ubiquitinated misfolded/unfolded proteins, and its inhibition results in cellular accumulation of protein aggregates. Intramuscle-fiber ubiquitinated multiprotein-aggregates are characteristic of sporadic inclusion-body myositis (s-IBM) muscle fibers. Two major types of aggregates exist, containing either amyloid-beta (A beta) or phosphorylated tau (p-tau). We have now asked whether abnormalities of the 26S proteasome contribute to s-IBM pathogenesis and whether the multiprotein aggregates have features of aggresomes. Using cultured human muscle fibers we also studied the effect of amyloid-beta precursor protein (A beta PP) overexpression on proteasome function and the influence of proteasome inhibition on aggresome formation. We report that in s-IBM muscle biopsies 26S proteasome subunits were immunodetected in the gamma-tubulin-associated aggresomes, which also contained A beta, p-tau, ubiquitin, and HSP70. In addition, a) expression of proteasome subunits was greatly increased, b) the 20S alpha proteasome subunit co-immunoprecipitated with A beta PP/A beta, and c) the three major proterasomal proteolytic activities were reduced. in cultured muscle fibers, A beta PP-overexpressing fibers displayed diminished proteasomal proteolytic activities, and addition of proteasome inhibitor strikingly increased aggresome formation. Accordingly, proteasome dysfunction in s-IBM muscle fibers may play a role in accumulation of misfolded, potentially cytotoxic proteins and may be induced by increased intracellular A beta PP/A beta.