Research on neurodegenerative disorders has been hampered by the limited access to patients' brain tissue and the absence of relevant physiological models with human neurons, accounting for the little success of clinical trials. Moreover, post-mortem samples cannot provide a detailed picture of the complex pathological mechanisms taking place throughout the course of the disease. This holds particularly true for Huntington's disease (HD), an incurable inherited brain disorder marked by a massive striatal degeneration due to abnormal accumulation of misfolded huntingtin protein. To characterize progressive human neurodegeneration in vivo, we transplanted induced pluripotent stem cell-derived human neural progenitor cells (hNPCs) from control (CTR-hNPCs) and HD patients (HD-hNPCs) into the striatum of neonatal wild-type mice. Implanted human cells were examined by immunohistochemistry and electron microscopy, and chimeric mice were subjected to behavioral testing. Most grafted hNPCs differentiated into striatal neurons that sent axonal projections to their natural targets and established synaptic connections within the host basal ganglia circuitry. HD-hNPCs first showed developmental abnormalities characterized by an increased proliferation and accelerated medium spiny neuron (MSN) differentiation, mimicking the initial striatal hypertrophy of child mutant huntingtin (mHTT) carriers. HD human striatal neurons progressively developed mHTT oligomers and aggregates, which primarily targeted mitochondria, endoplasmic reticulum and nuclear membrane to cause structural alterations. Five months after transplantation, selective death of human MSNs and striatal degeneration altered mouse behavior, suggesting disease propagation to non-mutated host cells. Histological analysis and co-culture experiments revealed that HD-hNPCs secreted extracellular vesicles containing soluble mHTT oligomers, which were internalized by mouse striatal neurons triggering cell death. Finally, in vivo pharmacological inhibition of the exosomal secretory pathway through sphingosine-1 phosphate receptor functional antagonism, limited the spreading of apoptosis within the host striatum. Our findings cast new light on human neurodegeneration, unveiling cell and non-cell autonomous mechanisms that drive HD progression in patients.

中文翻译：

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亨廷顿舞蹈病患者体内神经元的体内进行性变性揭示了人类特异性病理表型

神经退行性疾病的研究因无法进入患者的脑组织而受到限制，并且缺乏与人类神经元相关的生理模型，这在临床试验中几乎没有成功。此外，验尸样本无法提供整个疾病过程中发生的复杂病理机制的详细信息。对于亨廷顿氏病（HD）尤其如此，亨廷顿氏病（HD）是一种无法治愈的遗传性脑部疾病，其特征是由于错误折叠的亨廷顿蛋白的异常积累，导致大量纹状体变性。表征体内进行性人类神经变性，我们将来自对照（CTR-hNPC）和HD患者（HD-hNPC）的诱导性多能干细胞来源的人神经祖细胞（hNPC）移植到新生野生型小鼠的纹状体中。通过免疫组织化学和电子显微镜检查植入的人细胞，并对嵌合小鼠进行行为测试。大多数嫁接的hNPC分化为纹状体神经元，这些纹状体神经元将轴突投影发送至其自然靶标并在宿主基底神经节回路内建立了突触连接。HD-hNPCs首先表现出发育异常，其特征是增殖增加和中棘状神经元（MSN）分化加速，模仿了儿童突变型亨廷顿（mHTT）携带者的最初纹状体肥大。HD人类纹状体神经元逐渐形成mHTT低聚物和聚集体，主要针对线粒体，内质网和核膜引起结构改变。移植后五个月，人类MSNs的选择性死亡和纹状体变性改变了小鼠的行为，表明疾病传播至未突变的宿主细胞。组织学分析和共培养实验表明，HD-hNPCs分泌含有可溶性mHTT低聚物的细胞外囊泡，并被小鼠纹状体神经元内化，触发细胞死亡。最后，组织学分析和共培养实验表明，HD-hNPCs分泌含有可溶性mHTT低聚物的细胞外囊泡，并被小鼠纹状体神经元内化，触发细胞死亡。最后，组织学分析和共培养实验表明，HD-hNPCs分泌含有可溶性mHTT低聚物的细胞外囊泡，并被小鼠纹状体神经元内化，触发细胞死亡。最后，在体内药理学上通过鞘氨醇-1磷酸受体功能拮抗外泌体分泌途径的抑制作用，限制了宿主纹状体内细胞凋亡的扩散。我们的发现为人类神经变性提供了新的亮点，揭示了驱动患者高清进程的细胞和非细胞自主机制。