Deletion of the huntingtin polyglutamine stretch enhances neuronal autophagy and longevity in mice.
Deletion of the huntingtin polyglutamine stretch enhances neuronal autophagy and longevity in mice.
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DOI：
10.1371/journal.pgen.1000838
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发表时间：
2010-02-05
期刊：
影响因子：
4.5
通讯作者：
Zeitlin SO
中科院分区：
文献类型：
--
作者：
Zheng S;Clabough EB;Sarkar S;Futter M;Rubinsztein DC;Zeitlin SO
亨廷顿蛋白（huntingtin，htt）是IT 15基因的蛋白质产物，其中一段多聚谷氨酰胺的扩增导致了亨廷顿病（HD）。以前的研究中的作用，多聚谷氨酰胺拉伸（polyQ）的htt功能表明，它的长度可能会调节一个正常的htt功能参与调节能量稳态。在这里，我们表明，在HD的敲入小鼠模型（Hdh 140 Q/ΔQ）中表达缺乏其多聚谷氨酰胺链段的全长htt（ΔQ-htt），与HD模型小鼠（Hdh 140 Q/+）相比，显著减少了神经递质突变体htt聚集体，改善了运动/行为缺陷，并延长了寿命。HD模型表型的拯救伴随着脑中脂褐素水平的正常化和哺乳动物自噬标志物微管相关蛋白1轻链3-II（LC 3-II）的稳态水平的增加。我们还发现ΔQ-htt在体外的表达增加了自噬体的合成，并刺激了截短的N-末端htt聚集体的Atg 5依赖性清除。ΔQ-htt对自噬的作用最可能代表功能获得，因为体外全长野生型htt的过表达不会增加自噬体的合成。此外，HdhΔQ/ΔQ小鼠的寿命明显长于野生型小鼠，这表明自噬上调可能在由毒性细胞内聚集倾向蛋白引起的疾病中以及在正常哺乳动物中作为寿命延长剂都是有益的。亨廷顿蛋白（huntingtin，htt）是IT 15基因的蛋白产物，其氨基末端附近的一段谷氨酰胺的扩增是一种有害的突变，可导致亨廷顿病（HD）。相反，在这里，我们表明，htt的正常多聚谷氨酰胺片段（ΔQ-htt）的缺失是一种潜在的有益突变，当ΔQ-htt与具有HD突变的htt版本一起表达时，可以改善HD小鼠模型表型。此外，当在HD小鼠模型或非HD小鼠中表达时，ΔQ-htt表达可增强寿命。ΔQ-htt对寿命和HD模型表型的影响可能是由于自噬的增加，自噬是细胞中参与细胞组分和聚集蛋白质周转的主要再循环途径。根据我们的研究结果，我们建议开发能够刺激自噬的治疗药物可能有助于治疗神经退行性疾病，如HD，并延长寿命。
Expansion of a stretch of polyglutamine in huntingtin (htt), the protein product of the IT15 gene, causes Huntington's disease (HD). Previous investigations into the role of the polyglutamine stretch (polyQ) in htt function have suggested that its length may modulate a normal htt function involved in regulating energy homeostasis. Here we show that expression of full-length htt lacking its polyglutamine stretch (ΔQ-htt) in a knockin mouse model for HD (Hdh140Q/ΔQ), reduces significantly neuropil mutant htt aggregates, ameliorates motor/behavioral deficits, and extends lifespan in comparison to the HD model mice (Hdh140Q/+). The rescue of HD model phenotypes is accompanied by the normalization of lipofuscin levels in the brain and an increase in the steady-state levels of the mammalian autophagy marker microtubule-associate protein 1 light chain 3-II (LC3-II). We also find that ΔQ-htt expression in vitro increases autophagosome synthesis and stimulates the Atg5-dependent clearance of truncated N-terminal htt aggregates. ΔQ-htt's effect on autophagy most likely represents a gain-of-function, as overexpression of full-length wild-type htt in vitro does not increase autophagosome synthesis. Moreover, HdhΔQ/ΔQ mice live significantly longer than wild-type mice, suggesting that autophagy upregulation may be beneficial both in diseases caused by toxic intracellular aggregate-prone proteins and also as a lifespan extender in normal mammals. Expansion of a stretch of glutamines near the amino-terminus of huntingtin (htt), the protein product of the IT15 gene, is a deleterious mutation that causes Huntington's disease (HD). Here we show, in contrast, that deletion of htt's normal polyglutamine stretch (ΔQ-htt) is a potentially beneficial mutation that can ameliorate HD mouse model phenotypes when ΔQ-htt is expressed together with a version of htt with the HD mutation. In addition, ΔQ-htt expression can enhance longevity when expressed in either an HD mouse model or in non–HD mice. ΔQ-htt's effects on both lifespan and HD model phenotypes are likely due to an increase in autophagy, a major recycling pathway in cells that is involved in the turnover of cellular components, and aggregated protein. Based on our results, we suggest that development of therapeutic agents that can stimulate autophagy may help both in treating neurodegenerative disorders like HD and also in increasing longevity.
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影响因子：
3.9
作者：
Gerland, LM;Peyrol, S;Ffrench, M
通讯作者：
Ffrench, M
影响因子：
13.3
作者：
Atwal, Randy Singh;Truant, Ray
通讯作者：
Truant, Ray
影响因子：
5.7
作者：
Gao, Yong-Guang;Yan, Xian-Zhong;Hu, Hong-Yu
通讯作者：
Hu, Hong-Yu
p62/SQSTM1形成自噬降解的蛋白质聚集体，并对亨廷顿蛋白诱导的细胞死亡具有保护作用。
影响因子：
7.8
作者：
Bjorkoy, Geir;Lamark, Trond;Brech, Andreas;Outzen, Heidi;Perander, Maria;Overvatn, Aud;Stenmark, Harald;Johansen, Terje
通讯作者：
Johansen, Terje
DOI：
10.1037/h0077579
发表时间：
1979-01-01
期刊：
JOURNAL OF COMPARATIVE AND PHYSIOLOGICAL PSYCHOLOGY
影响因子：
--
作者：
BARNES, CA
通讯作者：
BARNES, CA