Abstract:
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an inherited neurodegenerative disease characterized by early-onset spasticity in the lower limbs, axonal-demyelinating sensorimotor peripheral neuropathy, and cerebellar ataxia. Our understanding of ARSACS (genetic basis, protein function, and disease mechanisms) remains partial. The integrative use of organelle-based quantitative proteomics and whole-genome analysis proposed in the present study allowed identifying the affected disease-specific pathways, upstream regulators, and biological functions related to ARSACS, which exemplify a rationale for the development of improved early diagnostic strategies and alternative treatment options in this rare condition that currently lacks a cure. Our integrated results strengthen the evidence for disease-specific defects related to bioenergetics and protein quality control systems and reinforce the role of dysregulated cytoskeletal organization in the pathogenesis of ARSACS.
摘要:
Charlevoix-Saguenay的常染色体隐性遗传性痉挛性共济失调(ARSACS)是一种遗传性神经退行性疾病,其特征是下肢早发性痉挛,轴突脱髓鞘性感觉运动周围神经病变,和小脑共济失调.我们对ARSACS(遗传基础,蛋白质功能,和疾病机制)仍然是部分的。本研究中提出的基于细胞器的定量蛋白质组学和全基因组分析的综合使用允许鉴定受影响的疾病特异性途径。上游监管机构,和ARSACS相关的生物学功能,这证明了在这种目前缺乏治愈方法的罕见疾病中,开发改进的早期诊断策略和替代治疗方案的理由。我们的综合结果加强了与生物能学和蛋白质质量控制系统相关的疾病特异性缺陷的证据,并加强了失调的细胞骨架组织在ARSACS发病机理中的作用。