Charlevoix-Saguenay常染色体隐性遗传性痉挛性共济失调(ARSACS)是一种早发性神经退行性疾病。2007年,一个新颖的基因座,SAX2,位于染色体17p13上,包含3个基因,锚蛋白重复序列和含FYVE结构域的1(ANKFY1),β-抑制素2(ARRB2)和驱动蛋白家族成员1C(KIF1C),与ARSACS有关。我们制作了Ankfy1杂合(Ankfy1/)小鼠,以建立动物模型并检查ARSACS的病理生理基础。转基因小鼠表现出异常的步态,具有进行性运动和小脑神经功能障碍,这让人联想到ARSACS。这些临床特征伴随着Purkinje细胞的早期发作和进行性丧失,其次是神经胶质增生。此外,Ankfy1功能的丧失导致Ankfy1/小鼠小脑中神经营养因子(NTFs)的异常表达。此外,从新生Ankfy1/小鼠培养的Purkinje细胞显示出较短的树突长度和减少的树突棘数量。重要的是,来自Ankfy1/+小鼠的小脑Purkinje细胞和转染慢病毒Ankfy1shRNA的细胞发生凋亡。我们建议转基因Ankfy1/小鼠是研究ARSACS发病机理和探索这种神经退行性疾病涉及的分子机制的有用模型。
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (
ARSACS) is an early-onset neurodegenerative disorder. In 2007, a novel locus, SAX2, which is located on chromosome 17p13 and contains 3 genes, ankyrin repeat and FYVE domain-containing 1 (ANKFY1), β-arrestin 2 (ARRB2) and kinesin family member 1C (KIF1C), was linked to
ARSACS. We generated Ankfy1 heterozygous (Ankfy1/+) mice to establish an animal model and examine the pathophysiological basis of
ARSACS. The transgenic mice displayed an abnormal gait with progressive motor and cerebellar nerve dysfunction that was highly reminiscent of
ARSACS. These clinical features were accompanied by an early-onset and progressive loss of Purkinje cells, followed by gliosis. Additionally, the loss of Ankfy1 function resulted in an abnormal expression of neurotrophic factors (NTFs) in the Ankfy1/+ mouse cerebellum. Moreover, Purkinje cells cultured from neonatal Ankfy1/+ mice exhibited a shorter dendritic length and decreased numbers of dendritic spines. Importantly, cerebellar Purkinje cells from Ankfy1/+ mice and cells transfected with a lentiviral Ankfy1 shRNA underwent apoptosis. We propose that transgenic Ankfy1/+ mice are a useful model for studying the pathogenesis of
ARSACS and for exploring the molecular mechanisms involved in this neurodegenerative disease.