In vivo progressive degeneration of Huntington's disease patient-derived neurons reveals human-specific pathological phenotypes

Research on neurodegenerative disorders has been hampered by the limited access to patients9 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 Huntington9s 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.