CECS/AFM, I-STEM, Corbeil-Essonnes 91100, France.
INSERM UMR 861, I-STEM, AFM, Corbeil-Essonnes 91100, France; Université Paris-Saclay, INSERM, Univ Evry, Institut des Cellules Souches pour le Traitement et l'Étude des Maladies Monogéniques, Corbeil-Essonnes 91100, France.
Am J Hum Genet. 2021 Nov 4;108(11):2171-2185. doi: 10.1016/j.ajhg.2021.10.001. Epub 2021 Oct 25.
Recent studies indicate that neurodegenerative processes that appear during childhood and adolescence in individuals with Wolfram syndrome (WS) occur in addition to early brain development alteration, which is clinically silent. Underlying pathological mechanisms are still unknown. We have used induced pluripotent stem cell-derived neural cells from individuals affected by WS in order to reveal their phenotypic and molecular correlates. We have observed that a subpopulation of Wolfram neurons displayed aberrant neurite outgrowth associated with altered expression of axon guidance genes. Selective inhibition of the ATF6α arm of the unfolded protein response prevented the altered phenotype, although acute endoplasmic reticulum stress response-which is activated in late Wolfram degenerative processes-was not detected. Among the drugs currently tried in individuals with WS, valproic acid was the one that prevented the pathological phenotypes. These results suggest that early defects in axon guidance may contribute to the loss of neurons in individuals with WS.
最近的研究表明，患有 W olfram 综合征（WS）的个体在儿童和青少年时期出现的神经退行性过程，除了早期大脑发育改变之外，这在临床上是无声的。潜在的病理机制尚不清楚。我们已经使用来自受 WS 影响的个体的诱导多能干细胞衍生的神经细胞，以揭示其表型和分子相关性。我们观察到，亚群 Wolfram 神经元显示出异常的神经突生长，与轴突导向基因的改变表达相关。未折叠蛋白反应的 ATF6α 分支的选择性抑制阻止了异常表型，尽管未检测到急性内质网应激反应——这在晚期 Wolfram 退行性过程中被激活。在目前尝试用于 WS 患者的药物中，丙戊酸是预防病理性表型的药物。这些结果表明，轴突导向的早期缺陷可能导致 WS 患者神经元的丧失。
