Soluble mutant huntingtin drives early human pathogenesis in Huntington’s disease

Miguez, Andrés, Gomis, Cinta, Vila, Cristina, Monguió-Tortajada, Marta, Fernández-García, Sara, Bombau, Georgina, Galofré, Mireia, García-Bravo, María, Sanders, Phil, Fernández-Medina, Helena, Poquet, Blanca, Salado-Manzano, Cristina, Roura, Santiago, Alberch, Jordi, Segovia, José Carlos, Allen, Nicholas D. ORCID: https://orcid.org/0000-0003-4009-186X, Borràs, Francesc E. and Canals, Josep M. 2023. Soluble mutant huntingtin drives early human pathogenesis in Huntington’s disease. Cellular and Molecular Life Sciences 80 (8) , 238. 10.1007/s00018-023-04882-w

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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. Graphical abstract:

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Biosciences
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Springer
ISSN:	1420-682X
Date of First Compliant Deposit:	4 August 2023
Date of Acceptance:	16 July 2023
Last Modified:	11 Oct 2023 20:35
URI:	https://orca.cardiff.ac.uk/id/eprint/161461

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