Mutations in the VPS13A gene leading to depletion of chorein protein are causative for Chorea Acanthocytosis (ChAc), a rare devastating disease, which is characterized by neurodegeneration mainly affecting the basal ganglia as well as deformation of erythrocytes. Studies on patient blood samples highlighted a dysregulation of Actin cytoskeleton caused by downregulation of the PI3K pathway and hyper-activation of Lyn-kinase, but to what extent these mechanisms are present and relevant in the affected neurons remains elusive. We studied the effects of the absence of chorein protein on the morphology and trafficking of lysosomal and mitochondrial compartments in ChAc patient-specific induced pluripotent stem cell-derived medium spiny neurons (MSNs). Numbers of both organelle types were reduced in ChAc MSNs. Mitochondrial length was shortened and their membrane potential showed significant hyperpolarization. In contrast to previous studies, showing Lyn kinase dependency of ChAc-associated pathological events in erythrocytes, pharmacological studies demonstrate that the impairment of mitochondria and lysosomes are independent of Lyn kinase activity. These data suggest that impairment in mitochondrial and lysosomal morphologies in MSNs is not mediated by a dysregulation of Lyn kinase and thus the pathological pathways in ChAc might be – at least in part – cell-type specific.

VPS13A基因中的突变导致藻蛋白的消耗，是造成少见的破坏性疾病Chrea Acanthocytosis（ChAc）的原因，该疾病的特征是神经退行性变，主要影响基底神经节以及红细胞的变形。对患者血液样本的研究强调，PI3K通路的下调和Lyn激酶的过度激活导致肌动蛋白细胞骨架失调，但是这些机制在受影响的神经元中存在和相关的程度仍然难以捉摸。我们研究了缺乏Chrein蛋白对ChAc患者特异性诱导的多能干细胞来源的中性多刺神经元（MSNs）的溶酶体和线粒体区室的形态和运输的影响。ChAc MSNs中两种细胞器类型的数量均减少。线粒体长度缩短，其膜电位显示出明显的超极化作用。与以前的研究相反，后者显示了红细胞中ChAc相关病理事件的Lyn激酶依赖性，药理研究表明，线粒体和溶酶体的损伤与Lyn激酶活性无关。这些数据表明，MSNs中线粒体和溶酶体形态的损害不是由Lyn激酶的失调介导的，因此ChAc中的病理途径可能至少部分是细胞类型特异性的。药理研究表明，线粒体和溶酶体的损伤与Lyn激酶活性无关。这些数据表明，MSNs中线粒体和溶酶体形态的损害不是由Lyn激酶的失调介导的，因此ChAc中的病理途径可能至少部分是细胞类型特异性的。药理研究表明，线粒体和溶酶体的损伤与Lyn激酶活性无关。这些数据表明，MSNs中线粒体和溶酶体形态的损害不是由Lyn激酶的失调介导的，因此ChAc中的病理途径可能至少部分是细胞类型特异性的。