Mutant γPKC found in spinocerebellar ataxia type 14 induces aggregate-independent maldevelopment of dendrites in primary cultured Purkinje cells
Mutant γPKC found in spinocerebellar ataxia type 14 induces aggregate-independent maldevelopment of dendrites in primary cultured Purkinje cells
复制标题
DOI：
10.1016/j.nbd.2008.10.013
复制
发表时间：
2009-02-01
影响因子：
6.1
通讯作者：
Sakai, Norio
中科院分区：
文献类型：
--
作者：
Seki, Takahiro;Shimahara, Takayuki;Sakai, Norio
脊髓小脑性共济失调14型（SCA 14）是一种常染色体显性遗传性神经退行性疾病，其蛋白激酶C γ（gamma PKC）基因存在错义突变。我们以前证明，SCA 14中发现的突变体γ PKC对聚集敏感，并诱导培养细胞系的凋亡。在本研究中，我们研究了突变型yPKC是否形成聚集体，以及突变型yPKC如何影响SCA 14患者退化的小脑浦肯野细胞（PC）的形态和存活。腺病毒转染的原代培养的表达突变体γ PKC-GFP的PC也有聚集体，并经历凋亡。长期的时间推移观察显示，PC具有消除突变体γ PKC-GFP聚集体的潜力。突变体γ PKC-GFP干扰PC树突的发育并减少突触形成，无论其聚集体的存在与否。在没有聚集体的PC中，突变体γ PKC-GFP形成可溶性寡聚体，导致刺激后突变体γ PKC-GFP的移动性降低和易位减弱。突变型yPKC的这些分子特性可能影响PCs树突状细胞的形态，并参与SCA 14的发病机制。(C)2008年爱思唯尔公司All rights reserved.
Missense mutations in protein kinase C gamma (gamma PKC) gene have been found in spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously demonstrated that mutant gamma PKC found in SCA14 is susceptible to aggregation and induces apoptosis in cultured cell lines. In the present study, we investigated whether mutant yPKC formed aggregates and how mutant yPKC affects the morphology and survival of cerebellar Purkinje cells (PCs), which are degenerated in SCA14 patients. Adenovirus-transfected primary cultured PCs expressing mutant gamma PKC-GFP also had aggregates and underwent apoptosis. Long-term time-lapse observation revealed that PCs have a potential to eliminate aggregates of mutant gamma PKC-GFP. Mutant gamma PKC-GFP disturbed the development of PC dendrites and reduced synapse formation, regardless of the presence or absence of its aggregates. In PCs without aggregates, mutant gamma PKC-GFP formed soluble oligomers, resulting in reduced mobility and attenuated translocation of mutant gamma PKC-GFP upon stimulation. These molecular properties of mutant yPKC might affect the dendritic morphology in PCs, and be involved in the pathogenesis of SCA14. (C) 2008 Elsevier Inc. All rights reserved.