p62/SQSTM1 Differentially Removes the Toxic Mutant Androgen Receptor via Autophagy and Inclusion Formation in a Spinal and Bulbar Muscular Atrophy Mouse Model
p62/SQSTM1 Differentially Removes the Toxic Mutant Androgen Receptor via Autophagy and Inclusion Formation in a Spinal and Bulbar Muscular Atrophy Mouse Model
复制标题
DOI：
10.1523/jneurosci.3021-12.2013
复制
发表时间：
2013-05-01
影响因子：
5.3
通讯作者：
Sobue, Gen
中科院分区：
文献类型：
--
作者：
Doi, Hideki;Adachi, Hiroaki;Sobue, Gen
多聚谷氨酰胺（polyQ）疾病是由致病基因中三核苷酸CAG重复序列扩增引起的遗传性神经退行性疾病。脊髓延髓肌萎缩症（SBMA）是一种遗传性运动神经元疾病，由雄激素受体（AR）内polyQ束扩张引起。p62是一种泛素和轻链3结合蛋白，已知其通过自噬和包涵体形成调节靶蛋白的降解。在这项研究中，我们研究了p62耗竭和过度表达对培养细胞和过度表达突变体AR的转基因小鼠模型的影响。在这里，我们表明，耗尽p62显着加剧运动表型和神经病理学结果，而过度表达p62保护突变体AR毒性SBMA小鼠。在SBMA小鼠模型中，p62的耗竭通过自噬降解的损伤显著增加了单体突变体AR和突变体AR蛋白复合物的水平。此外，p62过表达通过诱导细胞保护性包涵体形成改善SBMA小鼠表型。我们的研究结果表明，p62在SBMA发病机制中提供了两种不同的治疗靶点：（1）自噬依赖性降解和（2）突变AR的良性包含形成。
Polyglutamine (polyQ) diseases are inherited neurodegenerative disorders that are caused by the expansion of trinucleotide CAG repeats in the causative genes. Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease that is caused by the expansion of a polyQ tract within the androgen receptor (AR). p62 is a ubiquitin-and light-chain 3-binding protein that is known to regulate the degradation of targeted proteins via autophagy and inclusion formation. In this study, we examined the effects of p62 depletion and overexpression on cultured cells and in a transgenic mouse model that overexpressed the mutant AR. Here, we demonstrate that depletion of p62 significantly exacerbated motor phenotypes and the neuropathological outcome, whereas overexpression of p62 protected against mutant AR toxicity in SBMA mice. Depletion of p62 significantly increased the levels of monomeric mutant AR and mutant AR protein complexes in an SBMA mouse model via the impairment of autophagic degradation. In addition, p62 overexpression improved SBMA mouse phenotypes by inducing cytoprotective inclusion formation. Our results demonstrate that p62 provides two different therapeutic targets in SBMA pathogenesis: (1) autophagy-dependent degradation and (2) benevolent inclusion formation of the mutant AR.