Age-dependent decrease in chaperone activity impairs MANF expression, leading to Purkinje cell degeneration in inducible SCA17 mice.
Age-dependent decrease in chaperone activity impairs MANF expression, leading to Purkinje cell degeneration in inducible SCA17 mice.
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DOI：
10.1016/j.neuron.2013.12.002
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发表时间：
2014-01-22
期刊：
影响因子：
16.2
通讯作者：
Li S
中科院分区：
文献类型：
--
作者：
Yang S;Huang S;Gaertig MA;Li XJ;Li S
尽管蛋白质错误折叠介导的神经退行性疾病与衰老有关，但衰老如何导致选择性神经退行性疾病仍不清楚。我们建立了脊髓小脑性共济失调17（SCA 17）基因敲入小鼠，诱导表达一个拷贝的突变TATA盒结合蛋白（TBP）在不同年龄的他莫昔芬介导的Cre重组。我们发现，更多的突变TBP积累在老年小鼠，这种积累与年龄相关的Hsc 70和伴侣活性下降。同样，年龄较大的SCA 17小鼠经历了更早的神经系统症状发作和更严重的浦肯野细胞变性。突变TBP显示与XBP 1 s的关联减少，导致中脑星形胶质细胞源性神经营养因子（MANF）的转录减少，该因子在浦肯野细胞中富集。Hsc 70的表达改善了TBP-XBP 1 s相互作用和MANF的转录，并且MANF的过表达通过蛋白激酶C（PKC）依赖的信号传导改善了突变型TBP介导的浦肯野细胞变性。这些发现表明，与年龄相关的伴侣活性下降影响多聚谷氨酰胺蛋白的功能，这是重要的特定类型的神经元的活力。
Although protein-misfolding-mediated neurodegenerative diseases have been linked to aging, how aging contributes to selective neurodegeneration remains unclear. We established spinocerebellar ataxia 17 (SCA17) knockin mice that inducibly express one copy of mutant TATA box binding protein (TBP) at different ages by tamoxifen-mediated Cre recombination. We find that more mutant TBP accumulates in older mouse and that this accumulation correlates with age-related decreases in Hsc70 and chaperone activity. Consistently, older SCA17 mice experienced earlier neurological symptom onset and more severe Purkinje cell degeneration. Mutant TBP shows decreased association with XBP1s, resulting in the reduced transcription of mesencephalic astrocyte-derived neurotrophic factor (MANF), which is enriched in Purkinje cells. Expression of Hsc70 improves the TBP-XBP1s interaction and MANF transcription, and overexpression of MANF ameliorates mutant TBP-mediated Purkinje cell degeneration via protein kinase C (PKC)-dependent signaling. These findings suggest that the age-related decline in chaperone activity affects polyglutamine protein function that is important for the viability of specific types of neurons.