Alpha-synuclein preformed fibril-induced aggregation and dopaminergic cell death in cathepsin D overexpression and ZKSCAN3 knockout mice

Toni Mueller, Parker Jeffrey, Yecheng He, Xiaosen Ouyang, David Westbrook, Victor Darley-Usmar, Matthew S Goldberg, Laura Volpicelli-Daley, Jianhua Zhang
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Abstract

alpha-synuclein accumulation is recognized as a prominent feature in the majority of Parkinson disease cases and also occurs in a broad range of neurodegenerative disorders including Alzheimer disease. It has been shown that alpha-synuclein can spread from a donor cell to neighboring cells and thus propagate cellular damage, antagonizing the effectiveness of therapies such as transplantation of fetal or iPSC derived dopaminergic cells. As we and others previously have shown, insufficient lysosomal function due to genetic mutations or targeted disruption of cathepsin D can cause alpha-synuclein accumulation. We here investigated whether overexpression of cathepsin D or knockout (KO) of the transcriptional suppressor of lysosomal biogenesis ZKSCAN3 can attenuate propagation of alpha-synuclein aggregation and cell death. We examined dopaminergic neurodegeneration in the substantia nigra using stereology of tyrosine hydroxylase-immunoreactive cells 4 months and 6 months after intrastriatal injection of alpha-synuclein preformed fibrils or monomeric alpha-synuclein control in control, central nervous system (CNS)-cathepsin D overexpressing and CNS-specific ZKSCAN3 KO mice. We also examined pS129-alpha-synuclein aggregates in the substantia nigra, cortex, amygdala and striatum. The extent of dopaminergic neurodegeneration and pS129-alpha-synuclein aggregation in the brains of CNS-specific ZKSCAN3 knockout mice and CNS-cathepsin D overexpressing mice was similar to that observed in wild-type mice. Our results indicate that neither enhancing cathepsin D expression nor disrupting ZKSCAN3 in the CNS is sufficient to attenuate pS129-alpha-synuclein aggregate accumulation or dopaminergic neurodegeneration.
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在cathepsin D过表达和ZKSCAN3基因敲除小鼠体内,α-突触核蛋白预成纤维诱导聚集和多巴胺能细胞死亡
α-突触核蛋白积聚被认为是大多数帕金森病病例的一个突出特征,也会出现在包括阿尔茨海默病在内的多种神经退行性疾病中。研究表明,α-突触核蛋白可从供体细胞扩散到邻近细胞,从而传播细胞损伤,影响移植胎儿或 iPSC 衍生多巴胺能细胞等疗法的效果。正如我们和其他研究人员先前所显示的,由于基因突变或靶向干扰cathepsin D而导致溶酶体功能不足,可引起α-突触核蛋白的积累。我们在此研究了过表达 cathepsin D 或敲除(KO)溶酶体生物发生的转录抑制因子 ZKSCAN3 是否能减轻α-突触核蛋白聚集的传播和细胞死亡。我们在对照组、中枢神经系统(CNS)-酪蛋白酶D过表达组和中枢神经系统特异性ZKSCAN3 KO小鼠椎管内注射α-突触核蛋白预成纤维或单体α-突触核蛋白对照组4个月和6个月后,使用酪氨酸羟化酶免疫反应细胞的立体学方法检测了黑质中的多巴胺能神经变性。我们还检测了黑质、皮层、杏仁核和纹状体中的α-突触核蛋白聚合体。中枢神经系统特异性 ZKSCAN3 基因敲除小鼠和中枢神经系统酪蛋白酶 D 过表达小鼠大脑中多巴胺能神经变性和 pS129-α-synuclein 聚集的程度与野生型小鼠相似。我们的研究结果表明,在中枢神经系统中增强酪蛋白酶 D 的表达或破坏 ZKSCAN3 都不足以减轻 pS129-α-synuclein 聚集的积累或多巴胺能神经退行性变。
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