Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death
Accumulation of the authentic parkin substrate aminoacyl-tRNA synthetase cofactor, p38/JTV-1, leads to catecholaminergic cell death
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DOI：
10.1523/jneurosci.2172-05.2005
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发表时间：
2005-08-31
影响因子：
5.3
通讯作者：
Dawson, TM
中科院分区：
文献类型：
--
作者：
Ko, HS;von Coelln, R;Dawson, TM
常染色体隐性青少年帕金森氏症（AR-JP）是由帕金森氏基因功能缺失突变引起的。Parkin是一种环型E3泛素连接酶，负责泛素化和底物蛋白的降解，这在帕金森病（PD）中多巴胺神经元的存活中很重要。因此，神经毒性帕金底物的异常积累导致帕金功能丧失可能是帕金森氏症神经退行性变的原因。我们评估了迄今为止在无parkin小鼠中鉴定的已知parkin底物，以确定缺乏parkin是否会导致这些底物的积累。在这里，我们发现在年轻和年老的帕金小鼠中，只有氨基酰基trna合成酶辅助因子p38在腹侧中脑/后脑上调。与parkin敲除小鼠的上调一致，AR-JP和特发性PD和弥漫性路易体病的大脑也表现出p38水平升高。此外，p38与parkin和parkin泛素相互作用并靶向p38进行降解。此外，p38的过表达诱导细胞死亡，这种死亡随着肿瘤坏死因子- α治疗而增加，而帕金阻断了p38的促细胞死亡作用，而帕金家族相关突变体R42P未能挽救细胞死亡。我们进一步表明，腺病毒介导的p38在小鼠黑质中的过表达导致多巴胺能神经元的丢失。总之，我们的研究代表了我们对帕金功能理解的重大进展，因为它清楚地确定了p38是帕金的一个重要的真正的病理生理底物。此外，这些结果对了解PD神经退行性变的分子机制具有重要意义。
Autosomal-recessive juvenile parkinsonism (AR-JP) is caused by loss-of-function mutations of the parkin gene. Parkin, a RING-type E3 ubiquitin ligase, is responsible for the ubiquitination and degradation of substrate proteins that are important in the survival of dopamine neurons in Parkinson's disease (PD). Accordingly, the abnormal accumulation of neurotoxic parkin substrates attributable to loss of parkin function may be the cause of neurodegeneration in parkin-related parkinsonism. We evaluated the known parkin substrates identified to date in parkin null mice to determine whether the absence of parkin results in accumulation of these substrates. Here we show that only the aminoacyl-tRNA synthetase cofactor p38 is upregulated in the ventral midbrain/hindbrain of both young and old parkin null mice. Consistent with upregulation in parkin knock-out mice, brains of AR-JP and idiopathic PD and diffuse Lewy body disease also exhibit increased level of p38. In addition, p38 interacts with parkin and parkin ubiquitinates and targets p38 for degradation. Furthermore, overexpression of p38 induces cell death that increases with tumor necrosis factor-alpha treatment and parkin blocks the pro-cell death effect of p38, whereas the R42P, familial-linked mutant of parkin, fails to rescue cell death. We further show that adenovirus-mediated overexpression of p38 in the substantia nigra in mice leads to loss of dopaminergic neurons. Together, our study represents a major advance in our understanding of parkin function, because it clearly identifies p38 as an important authentic pathophysiologic substrate of parkin. Moreover, these results have important implications for understanding the molecular mechanisms of neurodegeneration in PD.