Reduction of mutant huntingtin accumulation and toxicity by lysosomal cathepsins D and B in neurons.
Reduction of mutant huntingtin accumulation and toxicity by lysosomal cathepsins D and B in neurons.
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DOI：
10.1186/1750-1326-6-37
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发表时间：
2011-06-01
影响因子：
15.1
通讯作者：
Zhang J
中科院分区：
文献类型：
--
作者：
Liang Q;Ouyang X;Schneider L;Zhang J
亨廷顿病是由含有多于36个polyQ重复的突变亨廷顿（mHtt）蛋白的聚集引起的。大自噬的上调被认为是降解突变亨廷顿蛋白的神经保护策略。然而，已显示大自噬起始在神经元中是高度有效的，而溶酶体活性是速率限制性的。溶酶体和其他蛋白酶在亨廷顿舞蹈症中的作用尚不清楚。一些研究表明，某些蛋白酶活性可能会导致毒性，而另一些则与保护作用一致。这些差异可能是由于多种机制造成的，包括不同蛋白酶产生的突变亨廷顿蛋白的特定中间消化产物的不同影响。这些观察结果表明，迫切需要研究突变亨廷顿蛋白积累和毒性中个别溶酶体酶上调的后果。在这项研究中，我们使用分子方法来提高溶酶体蛋白酶活性，并检查其对突变亨廷顿蛋白水平和毒性的影响。我们发现，溶酶体组织蛋白酶D和B的表达增强导致其酶活性增加，并减少全长和片段亨廷顿蛋白在转染的HEK细胞。此外，组织蛋白酶D或B的表达增强保护原代神经元免受突变型亨廷顿蛋白毒性的影响，并且它们的神经保护依赖于大自噬。这些观察结果证明了增强溶酶体组织蛋白酶在降低转染细胞中的突变亨廷顿蛋白水平和毒性方面的神经保护作用。他们强调了组织蛋白酶D或B通过巨自噬介导的神经保护的潜在重要性。
Huntington's disease is caused by aggregation of mutant huntingtin (mHtt) protein containing more than a 36 polyQ repeat. Upregulation of macroautophagy was suggested as a neuroprotective strategy to degrade mutant huntingtin. However, macroautophagy initiation has been shown to be highly efficient in neurons whereas lysosomal activities are rate limiting. The role of the lysosomal and other proteases in Huntington is not clear. Some studies suggest that certain protease activities may contribute to toxicity whereas others are consistent with protection. These discrepancies may be due to a number of mechanisms including distinct effects of the specific intermediate digestion products of mutant huntingtin generated by different proteases. These observations suggested a critical need to investigate the consequence of upregulation of individual lysosomal enzyme in mutant huntingtin accumulation and toxicity. In this study, we used molecular approaches to enhance lysosomal protease activities and examined their effects on mutant huntingtin level and toxicity. We found that enhanced expression of lysosomal cathepsins D and B resulted in their increased enzymatic activities and reduced both full-length and fragmented huntingtin in transfected HEK cells. Furthermore, enhanced expression of cathepsin D or B protected against mutant huntingtin toxicity in primary neurons, and their neuroprotection is dependent on macroautophagy. These observations demonstrate a neuroprotective effect of enhancing lysosomal cathepsins in reducing mutant huntingtin level and toxicity in transfected cells. They highlight the potential importance of neuroprotection mediated by cathepsin D or B through macroautophagy.
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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
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Tyynela, Jaana
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影响因子：
5.3
作者：
Boland, Barry;Kumar, Asok;Lee, Sooyeon;Platt, Frances M.;Wegiel, Jerzy;Yu, W. Haung;Nixon, Ralph A.
通讯作者：
Nixon, Ralph A.
影响因子：
13.3
作者：
Li XJ;Li H;Li S
通讯作者：
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影响因子：
14.8
作者：
Sarkar, Sovan;Perlstein, Ethan O.;Imarisio, Sara;Pineau, Sandra;Cordenier, Axelle;Maglathlin, Rebecca L.;Webster, John A.;Lewis, Timothy A.;O'Kane, Cahir J.;Schreiber, Stuart L.;Rubinsztein, David C.
通讯作者：
Rubinsztein, David C.