Elucidation of the Molecular Mechanism and Exploration of Novel Therapeutics for Spinocerebellar Ataxia Caused by Mutant Protein Kinase Cγ
Elucidation of the Molecular Mechanism and Exploration of Novel Therapeutics for Spinocerebellar Ataxia Caused by Mutant Protein Kinase Cγ
复制标题
DOI：
10.1254/jphs.11r04cp
复制
发表时间：
2011-07-01
影响因子：
3.5
通讯作者：
Sakai, Norio
中科院分区：
文献类型：
--
作者：
Seki, Takahiro;Adachi, Naoko;Sakai, Norio
脊髓小脑性共济失调(SCA)是一种遗传性神经退行性疾病，以小脑萎缩和进行性共济失调为特征，按遗传位点分为31种类型。最近，编码蛋白激酶Cγ(Gamma PKC)的PRKCG基因的错义突变被确定为SCA14的致病基因。为了探讨SCA14发病的分子机制，我们通过在细胞系和原代培养的小脑浦肯野细胞中表达突变的γ-PKC-GFP，研究了突变的γ-PKC如何导致小脑浦肯野细胞(PC)的神经变性。突变的Gamma-PKC容易聚集在细胞质中，导致泛素-蛋白酶体系统的损伤和细胞凋亡。此外，突变的Gamma PKC以非聚集的方式诱导培养的PC树突状细胞的异常发育。突变型γ-PKC寡聚化的迁移率降低显著减弱了刺激诱导的突变型γ-PKC在PC树突状细胞中的移位，从而导致信号转导减弱和PC树突状细胞形态不正确。这些结果提示突变的γ-PKC的寡聚和聚集导致PC树突状细胞发育和凋亡的异常，从而导致小脑功能障碍和SCA14的发病。我们筛选了改善这些细胞功能障碍的化学物质，并确定了几种化合物，包括海藻糖和刚果红，它们可能是治疗SCA14的新疗法。
Spinocerebellar ataxia (SCA) is an inherited neurodegenerative disorder that is characterized by cerebellar atrophy and progressive ataxia and is classified into 31 types by the genetic locus. Recently, missense mutations of PRKCG genes that code protein kinase C gamma (gamma PKC) have been identified as a causal gene of SCA14. To explore the molecular mechanism of SCA14 pathogenesis, we investigated how mutant gamma PKC causes the neurodegeneration of cerebellar Purkinje cells (PCs) by expressing mutant gamma PKC-GFP in cell lines and primary cultured PCs. Mutant gamma PKC was susceptible to aggregation in the cytoplasm, which led to an impairment of the ubiquitin-proteasome system and apoptosis. Furthermore, mutant gamma PKC induced improper dendritic development of cultured PCs in an aggregation-independent manner. Stimulation-induced translocation of mutant gamma PKC in PC dendrites was prominently attenuated by the reduced mobility of oligomerized mutant gamma PKC, which resulted in attenuated signal transduction and the improper morphology of PC dendrites. These findings suggested that the oligomerization and aggregation of mutant gamma PKC caused improper dendritic development and apoptosis of PCs, which led to cerebellar dysfunction and SCA14 pathogenesis. We screened the chemicals that improved these cellular dysfunctions and identified several compounds, including trehalose and Congo red, which could be novel therapeutics for SCA14.