PDF(Pubmed)
Abstract：
Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the SACS gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with Sacs knock-out (KO) mice and patient-derived fibroblasts suggested that SACSIN mutations inhibit the function of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction. We experimentally tested this hypothesis by genetically manipulating the mitochondrial fission/fusion equilibrium, creating double KO (DKO) mice that also lack positive (PP2A/Bβ2) and negative (PKA/AKAP1) regulators of Drp1. Neither promoting mitochondrial fusion (Bβ2 KO) nor fission (Akap1 KO) influenced progression of motor symptoms in Sacs KO mice. However, our studies identified profound learning and memory deficits in aged Sacs KO mice. Moreover, this cognitive impairment was rescued in a gene dose-dependent manner by deletion of the Drp1 inhibitor PKA/Akap1. Our results are inconsistent with mitochondrial dysfunction as a primary pathogenic mechanism in ARSACS. Instead, they imply that promoting mitochondrial fission may be beneficial at later stages of the disease when pathology extends to brain regions subserving learning and memory.
摘要：
Charlevoix-Saguenay（ARSACS）的常染色体隐性遗传性痉挛性共济失调是由SACS基因的功能丧失突变引起的，编码萨辛，推定的HSP70-HSP90共同伴侣。先前对Sacs敲除（KO）小鼠和患者来源的成纤维细胞的研究表明，SACSIN突变抑制了线粒体裂变酶动力蛋白相关蛋白1（Drp1）的功能。这又导致线粒体过度融合和功能障碍。我们通过基因操纵线粒体裂变/融合平衡实验检验了这一假设，创建双KO（DKO）小鼠，该小鼠也缺乏Drp1的阳性（PP2A/Bβ2）和阴性（PKA/AKAP1）调节因子。促进线粒体融合（Bβ2KO）和裂变（Akap1KO）均不影响SacsKO小鼠运动症状的进展。然而,我们的研究发现了老年SacsKO小鼠的深度学习和记忆缺陷。此外，通过删除Drp1抑制剂PKA/Akap1,以基因剂量依赖性方式挽救了这种认知障碍.我们的结果与线粒体功能障碍作为ARSACS的主要致病机制不一致。相反，它们暗示，当病理延伸到为学习和记忆服务的大脑区域时，促进线粒体裂变可能在疾病的后期阶段有益。
