Louit Aurélie, Beaudet Marie-Josée, Blais Mathieu, Gros-Louis François, Dupré Nicolas, Berthod François
LOEX, Centre de recherche du CHU de Québec-Université Laval, Quebec City, Quebec, Canada.
Department of Surgery, Faculty of Medicine, Université Laval, Quebec City, Quebec, Canada.
Stem Cells Int. 2023 Apr 15;2023:1496597. doi: 10.1155/2023/1496597. eCollection 2023.
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease mainly characterized by spasticity in the lower limbs and poor muscle control. The disease is caused by mutations in the gene leading in most cases to a loss of function of the sacsin protein, which is highly expressed in motor neurons and Purkinje cells. To investigate the impact of the mutated sacsin protein in these cells , induced pluripotent stem cell- (iPSC-) derived motor neurons and iPSC-derived Purkinje cells were generated from three ARSACS patients. Both types of iPSC-derived neurons expressed the characteristic neuronal markers 3-tubulin, neurofilaments M and H, as well as specific markers like Islet-1 for motor neurons, and parvalbumin or calbindin for Purkinje cells. Compared to controls, iPSC-derived mutated neurons expressed lower amounts of sacsin. In addition, characteristic neurofilament aggregates were detected along the neurites of both iPSC-derived neurons. These results indicate that it is possible to recapitulate , at least in part, the ARSACS pathological signature in vitro using patient-derived motor neurons and Purkinje cells differentiated from iPSCs. Such an personalized model of the disease could be useful for the screening of new drugs for the treatment of ARSACS.
魁北克-萨格奈常染色体隐性痉挛性共济失调（ARSACS）是一种早发性神经退行性疾病，主要特征为下肢痉挛和肌肉控制不佳。该疾病由基因突变引起，在大多数情况下会导致 sacsin 蛋白功能丧失，sacsin 蛋白在运动神经元和浦肯野细胞中高度表达。为了研究突变的 sacsin 蛋白在这些细胞中的影响，从三名 ARSACS 患者中生成了诱导多能干细胞（iPSC）衍生的运动神经元和 iPSC 衍生的浦肯野细胞。两种类型的 iPSC 衍生神经元均表达特征性神经元标志物βIII-微管蛋白、神经丝 M 和 H，以及运动神经元特异性标志物如胰岛-1，浦肯野细胞特异性标志物小白蛋白或钙结合蛋白。与对照相比，iPSC 衍生的突变神经元表达的 sacsin 量较低。此外，在两种 iPSC 衍生神经元的神经突中均检测到特征性神经丝聚集物。这些结果表明，使用患者来源的运动神经元和由 iPSC 分化而来的浦肯野细胞，至少可以部分地在体外重现 ARSACS 的病理特征。这种疾病的个性化模型可能有助于筛选治疗 ARSACS 的新药。
