Pircs, Karolina, Drouin-Ouellet, Janelle, Horváth, Vivien, Gil, Jeovanis, Rezeli, Melinda, Garza, Raquel, Grassi, Daniela A., Sharma, Yogita, St-Amour, Isabelle, Harris, Kate, and others. (2022) Distinct subcellular autophagy impairments in induced neurons from patients with Huntington's disease. Brain, 145 (9). pp. 3035-3057. ISSN 0006-8950. (doi:10.1093/brain/awab473) (KAR id:114594)
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Language: English 
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| Official URL: https://doi.org/10.1093/brain%2Fawab473 |
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Abstract
Huntington's disease 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 ageing humans. To address this, we generated induced neurons through direct reprogramming of human skin fibroblasts, which retain age-dependent epigenetic characteristics.
Huntington's disease induced neurons (HD-iNs) displayed profound deficits in autophagy, characterized 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 control induced neurons, 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 rationale for future development of autophagy activation therapies.
| Item Type: | Article |
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| DOI/Identification number: | 10.1093/brain/awab473 |
| Uncontrolled keywords: | Huntington's disease, autophagy, direct neural reprogramming, lentiviral vector, CRISPR interference |
| Subjects: | R Medicine > RM Therapeutics. Pharmacology |
| Institutional Unit: | Schools > Medway School of Pharmacy |
| Former Institutional Unit: |
There are no former institutional units.
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| Funders: |
NIHR Cambridge Biomedical Research Centre (https://ror.org/05m8dr349)
Wellcome Trust (https://ror.org/029chgv08) |
| Depositing User: | Romina Vuono |
| Date Deposited: | 08 May 2026 13:43 UTC |
| Last Modified: | 20 May 2026 02:43 UTC |
| Resource URI: | https://kar.kent.ac.uk/id/eprint/114594 (The current URI for this page, for reference purposes) |
University of Kent Author Information
Vuono, Romina.
| Creator's ORCID: |
 https://orcid.org/0000-0002-5162-3422
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