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2023-08-03

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cc-by (c) Miguez, Andrés et al., 2023
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/220784

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

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Recurs relacionat

https://doi.org/10.1007/s00018-023-04882-w

Resum

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.

Matèries

Cèl·lules mare, Malalties cerebrals, Corea de Huntington, Ratolins (Animals de laboratori), Oligòmers

Matèries (anglès)

Stem cells, Brain diseases, Huntington's chorea, Mice (Laboratory animals), Oligomers

Citació

Col·leccions

Articles publicats en revistes (Biomedicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

Citació

MIGUEZ, Andrés, et al. Soluble mutant huntingtin drives early human pathogenesis in Huntington's disease. Cellular and Molecular Life Sciences. 2023. Vol. 80, num. 8. ISSN 1420-682X. [consulted: 3 of August of 2026]. Available at: https://hdl.handle.net/2445/220784

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