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

Karolina Pircs, Janelle Drouin-Ouellet, Vivien Horváth, Jeovanis Gil, Melinda Rezeli, Raquel Garza, Daniela A Grassi, Yogita Sharma, Isabelle St-Amour, Kate Harris, Marie E Jönsson, Pia A Johansson, Romina Vuono, Shaline V Fazal, Thomas Stoker, Bob A Hersbach, Kritika Sharma, Jessica Lagerwall, Stina Lagerström, Petter StormSébastien S Hébert, György Marko-Varga, Malin Parmar, Roger A Barker, Johan Jakobsson

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)3035-3057
JournalBrain : a journal of neurology
Issue number9
Early online date2021 Dec 22
Publication statusPublished - 2022

Bibliographical note

© The Author(s) 2021. Published by Oxford University Press on behalf of the Guarantors of Brain.

Subject classification (UKÄ)

  • Neurosciences


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