表达突变TBP蛋白的少突胶质细胞在17型小脑脊髓共济失调(SCA17)发病中的作用

The polyglutamine diseases consist of nine neurodegenerative disorders including spinocerebellar ataxia type 17（SCA17）that is caused by a polyglutamine tract expansion in the TATA box-binding protein(TBP). How ubiquitously expressed polyglutamine-expanded mutant TBP(mTBP) proteins can selectivly cause marked cerebellar atrophy and Purkinje cell loss still under investigation. It became increasingly evident that oligodendrocytes accomplish a more important role in brain function than previously thought.It remains largely unknown whether and how mTBP in oligodendrocyte can contribute to the neurological symptoms of SCA17.As in this proposal, we intend to establish a new knock-in mouse model that selectively expresses mutant TBP in oligodendrocytes via loxp/cre recombination system. we will also express mTBP in oligodendrocytes in vitro and culture these cells with or without neurons.we intend to use animal behavioral study, immnohistochemisty, cell and molecular biology strategies to determine the role of mTBP expressed oligodendrocytes in the pathogenesis of SCA17. This study will allow us to discover some oligodendrocyte dependent neurological symptoms of polyQ-expansion diseases, which are usually characterized by mutant protein neurotoxicity, and shed light on the underlying mechanisms.This study will also provide new targets for developing diagnostical and therapeutical strategies.

九种多聚谷氨酰胺疾病之一的17型小脑脊髓共济失调（Spinocerebellar ataxia 17，SCA17）是因TATA盒结合蛋白（TATA box-binding protein，TBP）多聚谷氨酰胺异常扩增所致的遗传性神经退行性疾病。机体普遍表达的突变TBP(mTBP)如何导致以小脑萎缩和Purkinje细胞缺失为特征的SCA17一直是研究热点。少突胶质细胞对维持脑功能起重要作用。但是在少突胶质细胞表达的mTBP蛋白是否和怎样导致SCA17 的神经性症状仍不清楚。本课题拟运用loxp/cre重组系统建立选择性在少突胶质细胞表达mTBP的KI小鼠模型并结合SCA17KI小鼠模型、表达mTBP的少突胶质细胞培养及其与原代神经元混合培养，综合运用动物行为学、免疫组织化学，细胞及分子生物学技术，明确表达mTBP的少突胶质细胞在SCA17发病中的作用，为多聚谷氨酰胺疾病诊疗提供新的靶点。

九种多聚谷氨酰胺疾病之一的17型小脑脊髓共济失调（Spinocerebellar ataxia 17，SCA17）是由于TATA盒结合蛋白（TATA box -binding protein，TBP）多聚谷氨酰胺异常扩增所致的遗传性神经退行性疾病。机体普遍表达的突变TBP(mTBP）蛋白如何导致以小脑萎缩和Purkinje细胞缺失为首要特征的SCA17疾病机制至今未明。本研究发现在全身表达mTBP蛋白的TBPKI模型小鼠中，少突胶质细胞呈现形态异常, 髓鞘蛋白合成下降，提示少突胶质功能失调。本研究进而利用loxp/cre重组系统建立选择性在少突胶质细胞中表达mTBP的knock-in小鼠模型(Olig2-TBPKI),并结合表达mTBP的少突胶质细胞培养及其与正常神经元原代混合培养对少突胶质细胞与SCA17关联进行深入探索。我们的研究发现：1) 与正常小鼠相比，Olig2-TBPKI小鼠体重随年龄呈病理性下降，并伴随运动功能下降，老年小鼠出现精神行为异常； 2) Olig2-TBPKI小鼠少突胶质细胞髓鞘蛋白合成减少，脑内凋亡细胞增多，小脑Purkinje细胞缺失，呈现退行性改变； 3) 体外表达mTBP蛋白的少突胶质细胞形态异常，髓鞘蛋白合成减少，细胞凋亡增多，并导致与其共培养神经元神经退行性病变。总之，我们的研究表明，少突胶质细胞在SCA17型疾病发病过程中通过原发性及继发性功能失调，参与疾病的发生发展。

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