Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization.
Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization.
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DOI：
10.1016/j.celrep.2022.111580
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发表时间：
2022-11-01
期刊：
影响因子：
8.8
通讯作者：
中科院分区：
文献类型：
--
作者：
常染色体隐性遗传性痉挛共济失调是一种儿童期起病的小脑性共济失调，由编码糖蛋白的囊泡突变引起。ARSACS细胞表型包括线粒体功能障碍、中间丝结构紊乱和小脑浦肯野神经元进行性死亡。目前尚不清楚为什么这些缺陷是由于丧失了sacsin引起的，也不清楚为什么会表现为小脑性共济失调。在这里，我们在Sacsin基因敲除(KO)细胞中进行多组谱分析，并确定微管动力学的变化和焦点黏附(FA)蛋白的错误定位，包括多种整合素。通过靶向FA信号负调控因子PTEN，可以挽救FA结构、信号和功能的缺陷。ARSACS小鼠存在ITGA1在Purkinje神经元的错误定位和小脑深核(DCN)的突触结构紊乱。Sacsin相互作用组揭示Sacsin调节细胞骨架和突触黏附蛋白之间的相互作用。我们的发现表明，突触黏附蛋白运输中断是ARSACS分子缺陷的原因。Sacsin调节细胞骨架组织、微管动力学和蛋白运输在Sacsin基因敲除细胞中局部黏附结构、功能和信号受到影响小脑Purkinje神经元改变整合素定位和突触结构Romano等人。对ARSACS模型细胞的蛋白质图谱进行了全面的表征，发现Sacsin调节几个核心的细胞过程，包括调节蛋白质活性、蛋白质运输、细胞结构和突触黏附蛋白的定位。这些发现有助于解释为什么糖蛋白的丢失会导致神经变性和小脑性共济失调。
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a childhood-onset cerebellar ataxia caused by mutations in SACS, which encodes the protein sacsin. Cellular ARSACS phenotypes include mitochondrial dysfunction, intermediate filament disorganization, and progressive death of cerebellar Purkinje neurons. It is unclear why the loss of sacsin causes these deficits or why they manifest as cerebellar ataxia. Here, we perform multi-omic profiling in sacsin knockout (KO) cells and identify alterations in microtubule dynamics and mislocalization of focal adhesion (FA) proteins, including multiple integrins. Deficits in FA structure, signaling, and function can be rescued by targeting PTEN, a negative regulator of FA signaling. ARSACS mice possess mislocalization of ITGA1 in Purkinje neurons and synaptic disorganization in the deep cerebellar nucleus (DCN). The sacsin interactome reveals that sacsin regulates interactions between cytoskeletal and synaptic adhesion proteins. Our findings suggest that disrupted trafficking of synaptic adhesion proteins is a causal molecular deficit in ARSACS. Sacsin regulates cytoskeletal organization, microtubule dynamics, and protein trafficking Focal adhesion structure, function, and signaling are affected in sacsin knockout cells Cerebellar Purkinje neurons have altered integrin localization and synaptic structure Romano et al. comprehensively characterize the protein landscape of ARSACS model cells, finding that sacsin regulates several core cellular processes including regulation of protein activity, protein trafficking, cell structure, and localization of synaptic adhesion proteins. These findings help explain why the loss of sacsin causes neurodegeneration and cerebellar ataxia.
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