Soluble mutant huntingtin drives early human pathogenesis in Huntington’s disease
Andrés Miguez, Cinta Gomis, Cristina Vila, Marta Tortajada, Sara Fernández‐García, Georgina Bombau, Mireia Galofré, Marı́a Garcı́a-Bravo, Phil Sanders, Helena Fernández-Medina, Blanca Poquet, Cristina Salado-Manzano, Santiago Roura, Jordi Alberch, José C. Segovia, Nicholas D. Allen, Francesc E. Borràs, Josep M. Canals
Abstract
Huntington's disease (HD) is an incurable inherited brain disorder characterised by massive degeneration of striatal neurons, which correlates with abnormal accumulation of misfolded mutant huntingtin (mHTT) protein. Research on HD has been hampered by the inability to study early dysfunction and progressive degeneration of human striatal neurons in vivo. To investigate human pathogenesis in a physiologically relevant context, we transplanted human pluripotent stem cell-derived neural progenitor cells (hNPCs) from control and HD patients into the striatum of new-born mice. Most hNPCs differentiated into striatal neurons that projected to their target areas and established synaptic connexions within the host basal ganglia circuitry. Remarkably, HD human striatal neurons first developed soluble forms of mHTT, which primarily targeted endoplasmic reticulum, mitochondria and nuclear membrane to cause structural alterations. Furthermore, HD human cells secreted extracellular vesicles containing mHTT monomers and oligomers, which were internalised by non-mutated mouse striatal neurons triggering cell death. We conclude that interaction of mHTT soluble forms with key cellular organelles initially drives disease progression in HD patients and their transmission through exosomes contributes to spread the disease in a non-cell autonomous manner.