PARK2 encodes for the E3 ubiquitin ligase parkin and is implicated in the development of Parkinson's disease (PD). Although the neuroprotective role of parkin is well known, the mechanism of PARK2's function in neural stem differentiation has not yet been thoroughly studied. Co-expressions network analysis showed that synaptosomal-associated protein 25 (SNAP-25) and brain-derived neurotrophic factor (BDNF) were positively correlated with parkin, but negatively correlated with p21 in human patient brain. We investigated a link between the ubiquitin E3 ligase parkin and proteasomal degradation of p21 for the control of neural stem cell differentiation. We found that the neurogenesis was lowered in PARK2 knockout (KO) mice compared with non-tg mice. Expression of the marker protein for neural cell differentiation such as class III beta tubulin (TUBBIII), glial fibrillary acidic protein (GFAP) and neurofilament, as well as SNAP25 and BDNF, was down regulated in PARK2 KO mice. Associated with the loss of differentiation function, p21 protein was highly accumulated in the neural stem cells of PARK2 KO mice. We discovered that p21 directly binds with parkin and is ubiquitinated by parkin which resulted in the loss of cell differentiation ability. Introduction of p21 shRNA in PARK2 KO mice significantly rescued the differentiation efficacy as well as SNAP25 and BDNF expression. c-Jun N-terminal kinase (JNK) pathway is implicated in neurogenesis and p21 degradation. We also defined the decreased p21 ubiquitination and differentiation ability were reversed after treatment with JNK inhibitor, SP600125 in PARK2 KO mice derived neural stem cells. Thus, the present study indicated that parkin knockout inhibits neural stem cell differentiation by JNK-dependent proteasomal degradation of p21.

中文翻译：

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帕金森基因敲除可通过调节p21的蛋白酶体降解来抑制神经元发育。

PARK2编码E3泛素连接酶parkin，并与帕金森氏病（PD）的发生有关。尽管Parkin的神经保护作用是众所周知的，但尚未深入研究PARK2在神经干分化中的功能机制。共表达网络分析表明，在人类患者脑中，突触体相关蛋白25（SNAP-25）和脑源性神经营养因子（BDNF）与帕金蛋白呈正相关，而与p21呈负相关。我们调查了泛素E3连接酶Parkin和p21的蛋白酶体降解之间的联系，以控制神经干细胞的分化。我们发现与非tg小鼠相比，PARK2基因敲除（KO）小鼠的神经发生作用降低。在PARK2 KO小鼠中，用于神经细胞分化的标记蛋白（例如III类β微管蛋白（TUBBIII），神经胶质纤维酸性蛋白（GFAP）和神经丝）以及SNAP25和BDNF的表达下调。与分化功能丧失相关，p21蛋白在PARK2 KO小鼠的神经干细胞中高度积累。我们发现p21直接与parkin结合并被parkin泛素化，从而导致细胞分化能力的丧失。在PARK2 KO小鼠中引入p21 shRNA可以显着挽救其分化功效以及SNAP25和BDNF的表达。c-Jun N末端激酶（JNK）通路与神经发生和p21降解有关。我们还定义了JNK抑制剂治疗后p21泛素化的降低和分化能力的逆转，PARK2 KO小鼠中的SP600125来自神经干细胞。因此，本研究表明，Parkin基因敲除可通过p21的JNK依赖性蛋白酶体降解抑制神经干细胞的分化。