Over-expression of an inactive mutant cathepsin D increases endogenous alpha-synuclein and cathepsin B activity in SH-SY5Y cells.
Over-expression of an inactive mutant cathepsin D increases endogenous alpha-synuclein and cathepsin B activity in SH-SY5Y cells.
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DOI：
10.1111/jnc.12497
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发表时间：
2014-03
影响因子：
4.7
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Crabtree D;Dodson M;Ouyang X;Boyer-Guittaut M;Liang Q;Ballestas ME;Fineberg N;Zhang J
帕金森病（PD）是一种神经退行性运动障碍。PD的组织病理学包括称为路易体的蛋白质包涵体，其含有聚集的α-突触核蛋白。组织蛋白酶D（CD）是一种溶酶体蛋白酶，先前已证明在体内细胞系和小鼠脑中切割α-突触核蛋白并降低其毒性。在这里，我们表明，药理学抑制CD，或引入无催化活性的突变CD导致CD活性降低和组织蛋白酶B活性增加，这表明可能的补偿反应抑制CD活性。然而，这种增加的组织蛋白酶B活性不足以维持α-突触核蛋白的降解，如内源性α-突触核蛋白的蓄积所证明的。有趣的是，LC 3、LAMP 1和LAMP 2（参与自噬-溶酶体活性的蛋白质）的水平以及通过LysoTracker流式细胞术评估的总溶酶体质量均未发生变化。自噬通量和蛋白酶体活性在过度表达野生型CD与突变型CD的细胞之间均无差异。这些观察结果表明，α-突触核蛋白稳态中多巴胺能细胞中内源性CD活性的关键调节作用不能通过增加组织蛋白酶B来补偿。这些数据支持增强CD功能以减弱α-突触核蛋白蓄积作为对抗突触核蛋白病发展的治疗策略的潜在需求。
Parkinson’s disease (PD) is a neurodegenerative movement disorder. The histopathology of PD comprises proteinaceous inclusions known as Lewy bodies, which contains aggregated α-synuclein. Cathepsin D (CD) is a lysosomal protease previously demonstrated to cleave α-synuclein and decrease its toxicity in both cell lines and mouse brains in vivo. Here we show that pharmacological inhibition of CD, or introduction of catalytically inactive mutant CD resulted in decreased CD activity and increased cathepsin B activity, suggesting a possible compensatory response to inhibition of CD activity. However, this increased cathepsin B activity was not sufficient to maintain α-synuclein degradation, as evidenced by the accumulation of endogenous α-synuclein. Interestingly, the levels of LC3, LAMP1 and LAMP2, proteins involved in autophagy-lysosomal activities, as well as total lysosomal mass as assessed by LysoTracker flow cytometry, were unchanged. Neither autophagic flux nor proteasomal activities differ between cells over expressing wildtype versus mutant CD. These observations point to a critical regulatory role for that endogenous CD activity in dopaminergic cells in α-synuclein homeostasis which cannot be compensated for by increased Cathepsin B. These data support the potential need to enhance CD function in order to attenuate α-synuclein accumulation as a therapeutic strategy against development of synucleinopathy.
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DOI：
10.1083/jcb.201003122
发表时间：
2010-09-20
期刊：
The Journal of cell biology
影响因子：
--
作者：
Winslow AR;Chen CW;Corrochano S;Acevedo-Arozena A;Gordon DE;Peden AA;Lichtenberg M;Menzies FM;Ravikumar B;Imarisio S;Brown S;O'Kane CJ;Rubinsztein DC
通讯作者：
Rubinsztein DC
影响因子：
3.6
作者：
Qiao L;Hamamichi S;Caldwell KA;Caldwell GA;Yacoubian TA;Wilson S;Xie ZL;Speake LD;Parks R;Crabtree D;Liang Q;Crimmins S;Schneider L;Uchiyama Y;Iwatsubo T;Zhou Y;Peng L;Lu Y;Standaert DG;Walls KC;Shacka JJ;Roth KA;Zhang J
通讯作者：
Zhang J
影响因子：
3.6
作者：
Cullen, Valerie;Lindfors, Maria;Ng, Juliana;Paetau, Anders;Swinton, Erika;Kolodziej, Piotr;Boston, Heather;Saftig, Paul;Woulfe, John;Feany, Mel B.;Myllykangas, Liisa;Schlossmacher, Michael G.;Tyynela, Jaana
通讯作者：
Tyynela, Jaana
影响因子：
7.4
作者：
Dodson, Matthew;Darley-Usmar, Victor;Zhang, Jianhua
通讯作者：
Zhang, Jianhua
DOI：
10.1042/bj20111451
发表时间：
2012-01-15
期刊：
The Biochemical journal
影响因子：
--
作者：
Lee J;Giordano S;Zhang J
通讯作者：
Zhang J