Distinct subcellular autophagy impairments in induced neurons from patients with Huntington's disease
| Autor: | 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 Storm, Sébastien S Hébert, György Marko-Varga, Malin Parmar, Roger A Barker, Johan Jakobsson |
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| Přispěvatelé: | Pircs, Karolina [0000-0001-8281-4785], Jakobsson, Johan [0000-0003-0669-7673], Apollo - University of Cambridge Repository |
| Rok vydání: | 2022 |
| Předmět: |
Adult
Neurons congenital hereditary and neonatal diseases and abnormalities autophagy Huntingtin Protein lentiviral vector Huntington's disease Neurodegenerative Diseases nervous system diseases Huntington Disease nervous system mental disorders Humans Neurology (clinical) CRISPR interference direct neural reprogramming |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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