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Distinct sub-cellular autophagy impairments occur independently of protein aggregation in induced neurons from patients with Huntington’s disease

View ORCID ProfileKarolina Pircs, View ORCID ProfileJanelle Drouin-Ouellet, View ORCID ProfileJeovanis Gil, View ORCID ProfileMelinda Rezeli, Daniela A. Grassi, Raquel Garza, Yogita Sharma, View ORCID ProfileIsabelle St-Amour, View ORCID ProfileMarie E. Jönsson, Pia A. Johansson, Kate Harris, Romina Vuono, Thomas Stoker, View ORCID ProfileBob A. Hersbach, View ORCID ProfileKritika Sharma, Jessica Lagerwall, Stina Lagerström, Petter Storm, Vivien Horváth, Sébastien S. Hébert, György Marko-Varga, View ORCID ProfileMalin Parmar, View ORCID ProfileRoger A. Barker, View ORCID ProfileJohan Jakobsson
doi: https://doi.org/10.1101/2021.03.01.433433
Karolina Pircs
1Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
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Janelle Drouin-Ouellet
2Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada
3Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
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Jeovanis Gil
4Oncology and Pathology, Kamprad Lab, Lund University, Lund, Sweden
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Melinda Rezeli
5Clinical Protein Science and Imaging, Department of Biomedical Engineering, Lund University, Lund, Sweden
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Daniela A. Grassi
1Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
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Raquel Garza
1Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
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Yogita Sharma
1Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
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Isabelle St-Amour
6Axe Neurosciences, Centre de recherche du CHU de Québec – Université Laval, CHUL, Québec, QC G1V 4G2, Canada
7CERVO Brain Research Center – Université Laval, Québec City, QC, G1J 2G3, Canada
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Marie E. Jönsson
1Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
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Pia A. Johansson
1Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
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Kate Harris
8John van Geest Centre for Brain Repair & Department of Neurology, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB2 0PY, UK
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Romina Vuono
8John van Geest Centre for Brain Repair & Department of Neurology, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB2 0PY, UK
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Thomas Stoker
8John van Geest Centre for Brain Repair & Department of Neurology, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB2 0PY, UK
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Bob A. Hersbach
1Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
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Kritika Sharma
1Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
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Jessica Lagerwall
1Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
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Stina Lagerström
1Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
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Petter Storm
3Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
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Vivien Horváth
1Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
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Sébastien S. Hébert
6Axe Neurosciences, Centre de recherche du CHU de Québec – Université Laval, CHUL, Québec, QC G1V 4G2, Canada
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György Marko-Varga
4Oncology and Pathology, Kamprad Lab, Lund University, Lund, Sweden
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Malin Parmar
3Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
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Roger A. Barker
3Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
8John van Geest Centre for Brain Repair & Department of Neurology, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB2 0PY, UK
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Johan Jakobsson
1Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, 221 84 Lund, Sweden
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  • For correspondence: johan.jakobsson@med.lu.se
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Abstract

Huntington’s disease (HD) is a neurodegenerative disorder caused by CAG expansions in the huntingtin (HTT) gene. Modelling HD has remained challenging, as rodent and cellular models poorly recapitulate the disease. 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. The neurite-specific alterations in autophagy resulted in shorter, thinner and fewer neurites presented by 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 neuronal autophagy. In summary, our work identifies a distinct subcellular autophagy impairment in aged patient derived HD-neurons and provides a new rational for future development of autophagy activation therapies.

Competing Interest Statement

M.P., J.J. and J.DO. are co-inventors of the patent application PCT/EP2018/ 062261 owned by New York Stem Cell Foundation. M.P. is the owner of Parmar Cells AB.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted March 02, 2021.
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Distinct sub-cellular autophagy impairments occur independently of protein aggregation in induced neurons from patients with Huntington’s disease
Karolina Pircs, Janelle Drouin-Ouellet, Jeovanis Gil, Melinda Rezeli, Daniela A. Grassi, Raquel Garza, Yogita Sharma, Isabelle St-Amour, Marie E. Jönsson, Pia A. Johansson, Kate Harris, Romina Vuono, Thomas Stoker, Bob A. Hersbach, Kritika Sharma, Jessica Lagerwall, Stina Lagerström, Petter Storm, Vivien Horváth, Sébastien S. Hébert, György Marko-Varga, Malin Parmar, Roger A. Barker, Johan Jakobsson
bioRxiv 2021.03.01.433433; doi: https://doi.org/10.1101/2021.03.01.433433
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Distinct sub-cellular autophagy impairments occur independently of protein aggregation in induced neurons from patients with Huntington’s disease
Karolina Pircs, Janelle Drouin-Ouellet, Jeovanis Gil, Melinda Rezeli, Daniela A. Grassi, Raquel Garza, Yogita Sharma, Isabelle St-Amour, Marie E. Jönsson, Pia A. Johansson, Kate Harris, Romina Vuono, Thomas Stoker, Bob A. Hersbach, Kritika Sharma, Jessica Lagerwall, Stina Lagerström, Petter Storm, Vivien Horváth, Sébastien S. Hébert, György Marko-Varga, Malin Parmar, Roger A. Barker, Johan Jakobsson
bioRxiv 2021.03.01.433433; doi: https://doi.org/10.1101/2021.03.01.433433

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