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，除了早期大脑发育改变外，Wolfram 综合征 (WS) 患者在儿童期和青春期出现的神经退行性过程也会发生，这在临床上是无声的。潜在的病理机制仍然未知。我们使用了来自受 WS 影响的个体的诱导多能干细胞衍生的神经细胞，以揭示它们的表型和分子相关性。我们观察到 Wolfram 神经元的一个亚群表现出与轴突引导基因表达改变相关的异常神经突生长。尽管未检测到在晚期 Wolfram 退行性过程中激活的急性内质网应激反应，但对未折叠蛋白反应的 ATF6α 臂的选择性抑制阻止了表型的改变。在目前在 WS 患者中试用的药物中，丙戊酸是阻止病理表型的药物。这些结果表明，轴突导向的早期缺陷可能导致 WS 个体神经元的损失。