Reduction of RPT6/S8 (a Proteasome Component) and Proteasome Activity in the Cortex is Associated with Cognitive Impairment in Lewy Body Dementia.
Reduction of RPT6/S8 (a Proteasome Component) and Proteasome Activity in the Cortex is Associated with Cognitive Impairment in Lewy Body Dementia.
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DOI：
10.3233/jad-160946
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发表时间：
2017
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影响因子：
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通讯作者：
Whitfield DR
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文献类型：
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作者：
Alghamdi A;Vallortigara J;Howlett DR;Broadstock M;Hortobágyi T;Ballard C;Thomas AJ;O'Brien JT;Aarsland D;Attems J;Francis PT;Whitfield DR
路易体痴呆是第二常见的神经退行性痴呆，其病理特征是α-突触核蛋白阳性的细胞质包涵体，除了突触丧失外，还伴有不同数量的淀粉样蛋白-β (Aβ)和过度磷酸化的tau （tau）聚集体。功能失调的泛素蛋白酶体系统（UPS）是负责清除短寿命蛋白的主要蛋白水解途径，可能是疾病进展和α-突触核蛋白聚集体形成的介导因素。在本研究中，我们测定了UPS的一个关键组成部分，19S调控复合体的RPT6亚基的蛋白表达。此外，还分析了主要的蛋白水解样（胰凝乳蛋白酶-和PGPH-）活性。从帕金森病痴呆（PDD, n = 31）、路易体痴呆（DLB, n = 44）、阿尔茨海默病（AD, n = 16）和对照组（n = 24）脑中额叶（Brodmann, BA9）、下顶叶（BA40）和前扣带（BA24）脑回皮层中选取感兴趣的区域。临床和病理资料包括MMSE评分。与对照组相比，DLB、PDD和AD的特征是前额叶皮层和顶叶皮层的RPT6显著降低（单因素方差分析，p < 0.001； Bonferroni事后检验）。前额叶、顶叶皮层和前扣带回的RPT6水平与认知障碍有很强的相关性（p = 0.001、p = 0.001和p = 0.008）。这些发现强调了UPS在路易体痴呆中的作用，并表明靶向UPS可能有可能减缓或减少DLB和PDD患者认知功能障碍的进展。
Lewy body dementia is the second most common neurodegenerative dementia and is pathologically characterized by α-synuclein positive cytoplasmic inclusions, with varying amounts of amyloid-β (Aβ) and hyperphosphorylated tau (tau) aggregates in addition to synaptic loss. A dysfunctional ubiquitin proteasome system (UPS), the major proteolytic pathway responsible for the clearance of short lived proteins, may be a mediating factor of disease progression and of the development of α-synuclein aggregates. In the present study, protein expression of a key component of the UPS, the RPT6 subunit of the 19S regulatory complex was determined. Furthermore, the main proteolytic-like (chymotrypsin- and PGPH-) activities have also been analyzed. The middle frontal (Brodmann, BA9), inferior parietal (BA40), and anterior cingulate (BA24) gyrus’ cortex were selected as regions of interest from Parkinson’s disease dementia (PDD, n = 31), dementia with Lewy bodies (DLB, n = 44), Alzheimer’s disease (AD, n = 16), and control (n = 24) brains. Clinical and pathological data available included the MMSE score. DLB, PDD, and AD were characterized by significant reductions of RPT6 (one-way ANOVA, p < 0.001; Bonferroni post hoc test) in prefrontal cortex and parietal cortex compared with controls. Strong associations were observed between RPT6 levels in prefrontal, parietal cortex, and anterior cingulate gyrus and cognitive impairment (p = 0.001, p = 0.001, and p = 0.008, respectively). These findings highlight the involvement of the UPS in Lewy body dementia and indicate that targeting the UPS may have the potential to slow down or reduce the progression of cognitive impairment in DLB and PDD.