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

Pircs, Karolina LU orcid ; Drouin-Ouellet, Janelle LU ; Horváth, Vivien LU orcid ; Gil, Jeovanis LU ; Rezeli, Melinda LU orcid ; Garza, Raquel LU orcid ; Grassi, Daniela A LU ; Sharma, Yogita LU ; St-Amour, Isabelle and Harris, Kate , et al. (2022) In Brain : a journal of neurology 145(9). p.3035-3057
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Brain : a journal of neurology
volume
145
issue
9
pages
3035 - 3057
publisher
Oxford University Press
external identifiers
  • scopus:85138449514
  • pmid:34936701
ISSN
1460-2156
DOI
10.1093/brain/awab473
language
English
LU publication?
yes
additional info
© The Author(s) 2021. Published by Oxford University Press on behalf of the Guarantors of Brain.
id
7b6bcad7-d1ac-49f3-b38e-2624e13c2988
date added to LUP
2022-03-03 15:23:20
date last changed
2024-06-28 20:57:28
@article{7b6bcad7-d1ac-49f3-b38e-2624e13c2988,
  abstract     = {{<p>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.</p>}},
  author       = {{Pircs, Karolina and Drouin-Ouellet, Janelle and Horváth, Vivien and Gil, Jeovanis and Rezeli, Melinda and Garza, Raquel and Grassi, Daniela A and Sharma, Yogita and St-Amour, Isabelle and Harris, Kate and Jönsson, Marie E and Johansson, Pia A and Vuono, Romina and Fazal, Shaline V and Stoker, Thomas and Hersbach, Bob A and Sharma, Kritika and Lagerwall, Jessica and Lagerström, Stina and Storm, Petter and Hébert, Sébastien S and Marko-Varga, György and Parmar, Malin and Barker, Roger A and Jakobsson, Johan}},
  issn         = {{1460-2156}},
  language     = {{eng}},
  number       = {{9}},
  pages        = {{3035--3057}},
  publisher    = {{Oxford University Press}},
  series       = {{Brain : a journal of neurology}},
  title        = {{Distinct subcellular autophagy impairments in induced neurons from patients with Huntington's disease}},
  url          = {{http://dx.doi.org/10.1093/brain/awab473}},
  doi          = {{10.1093/brain/awab473}},
  volume       = {{145}},
  year         = {{2022}},
}