Distinct subcellular autophagy impairments in induced neurons from Huntington's disease patients.

TitleDistinct subcellular autophagy impairments in induced neurons from Huntington's disease patients.
Publication TypeJournal Article
Year of Publication2021
AuthorsPircs, K, Drouin-Ouellet, J, Horváth, V, Gil, J, Rezeli, M, Garza, R, Grassi, DA, Sharma, Y, St-Amour, I, Harris, K, Jönsson, ME, Johansson, PA, Vuono, R, Fazal, SV, Stoker, T, Hersbach, BA, Sharma, K, Lagerwall, J, Lagerström, S, Storm, P, Hébert, SS, Marko-Varga, G, Parmar, M, Barker, RA, Jakobsson, J
JournalBrain
Date Published2021 Dec 22
ISSN1460-2156
Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling Huntington's disease is challenging, as rodent and cellular models poorly recapitulate the disease as seen in aging humans. To address this, we generated induced neurons (iNs) through direct reprogramming of human skin fibroblasts, which retain age-dependent epigenetic characteristics. HD-iNs displayed profound deficits in autophagy, characterised by reduced transport of late autophagic structures from the neurites to the soma. These neurite-specific alterations in autophagy resulted in shorter, thinner and fewer neurites specifically in HD-iNs. CRISPRi-mediated silencing of HTT did not rescue this phenotype but rather resulted in additional autophagy alterations in ctrl-iNs, highlighting the importance of wild type HTT in normal neuronal autophagy. In summary, our work identifies a distinct subcellular autophagy impairment in adult patient derived Huntington's disease neurons and provides a new rational for future development of autophagy activation therapies.

DOI10.1093/brain/awab473
Alternate JournalBrain
PubMed ID34936701
Grant ListMC_PC_17230 / MRC_ / Medical Research Council / United Kingdom