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Genetic Disruption of WASHC4 Drives Endo-lysosomal Dysfunction and Cognitive-Movement Impairments in Mice and Humans
bioRxiv - Cell Biology Pub Date : 2020-08-06 , DOI: 10.1101/2020.08.06.239517
Jamie L. Courtland , Tyler W. A. Bradshaw , Greg Waitt , Erik J. Soderblom , Tricia Ho , Anna Rajab , Ricardo Vancini , Hwan Kim , Scott H. Soderling

Mutation of the WASH complex subunit, SWIP, is implicated in human intellectual disability, but the cellular etiology of this association is unknown. We identify the neuronal WASH complex proteome, revealing a network of endosomal proteins. To uncover how dysfunction of endosomal SWIP leads to disease, we generate a mouse model of the human WASHC4c.3056C>G mutation. Quantitative spatial proteomics analysis of SWIPP1019R mouse brain reveals that this mutation destabilizes the WASH complex and uncovers significant perturbations in both endosomal and lysosomal pathways. Cellular and histological analyses confirm that SWIPP1019R results in endo-lysosomal disruption and uncover indicators of neurodegeneration. We find that SWIPP1019R not only impacts cognition, but also causes significant progressive motor deficits in mice. Remarkably, a retrospective analysis of SWIPP1019R patients confirms motor deficits in humans. Combined, these findings support the model that WASH complex destabilization, resulting from SWIPP1019R, drives cognitive and motor impairments via endo-lysosomal dysfunction in the brain.

中文翻译:

WASHC4的基因破坏驱动小鼠和人类的内溶酶体功能障碍和认知运动障碍。

WASH复杂亚基SWIP的突变与人类智力障碍有关,但这种关联的细胞病因尚不清楚。我们确定了神经元的WASH复杂蛋白质组,揭示了内体蛋白网络。为了揭示内体SWIP功能障碍如何导致疾病,我们生成了人WASHC4c.3056C> G突变的小鼠模型。SWIPP1019R小鼠大脑的定量空间蛋白质组学分析表明,此突变使WASH复合物不稳定,并在内体和溶酶体途径中均表现出明显的扰动。细胞和组织学分析证实,SWIPP1019R导致内溶酶体破坏,并揭示神经变性的指标。我们发现SWIPP1019R不仅影响认知,而​​且还会在小鼠中引起明显的进行性运动缺陷。值得注意的是 对SWIPP1019R患者的回顾性分析证实了人类的运动缺陷。综上所述,这些发现支持了SWIPP1019R导致WASH复杂失稳的模型,它通过脑内溶酶体功能障碍驱动认知和运动障碍。
更新日期:2020-08-08
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