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

Autor:	Pircs K; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, S-221 84 Lund, Sweden., Drouin-Ouellet J; Faculty of Pharmacy, Université de Montréal, Montreal, QC H3T 1J4, Canada.; Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, BMC A11 and B10, Lund University, S-221 84 Lund, Sweden., Horváth V; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, S-221 84 Lund, Sweden., Gil J; Oncology and Pathology, Kamprad Lab, Department of Clinical Sciences, Lund University, S-221 85 Lund, Sweden., Rezeli M; Clinical Protein Science and Imaging, Department of Biomedical Engineering, Lund University, S-221 85 Lund, Sweden., Garza R; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, S-221 84 Lund, Sweden., Grassi DA; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, S-221 84 Lund, Sweden., Sharma Y; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, S-221 84 Lund, Sweden., St-Amour I; Axe Neurosciences, Centre de recherche du CHU de Québec, Université Laval, CHUL, Québec, QC, G1E 6W2, Canada.; CERVO Brain Research Center, Université Laval, Québec, QC, G1E 1T2, Canada., Harris K; Wellcome-MRC Cambridge Stem Cell Institute and John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB2 0PY, UK., Jönsson ME; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, S-221 84 Lund, Sweden., Johansson PA; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, S-221 84 Lund, Sweden., Vuono R; Wellcome-MRC Cambridge Stem Cell Institute and John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB2 0PY, UK., Fazal SV; Wellcome-MRC Cambridge Stem Cell Institute and John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB2 0PY, UK., Stoker T; Wellcome-MRC Cambridge Stem Cell Institute and John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB2 0PY, UK., Hersbach BA; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, S-221 84 Lund, Sweden., Sharma K; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, S-221 84 Lund, Sweden., Lagerwall J; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, S-221 84 Lund, Sweden., Lagerström S; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, S-221 84 Lund, Sweden., Storm P; Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, BMC A11 and B10, Lund University, S-221 84 Lund, Sweden., Hébert SS; Axe Neurosciences, Centre de recherche du CHU de Québec, Université Laval, CHUL, Québec, QC, G1E 6W2, Canada., Marko-Varga G; Oncology and Pathology, Kamprad Lab, Department of Clinical Sciences, Lund University, S-221 85 Lund, Sweden., Parmar M; Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, BMC A11 and B10, Lund University, S-221 84 Lund, Sweden., Barker RA; Developmental and Regenerative Neurobiology, Department of Experimental Medical Science, Wallenberg Neuroscience Center, Division of Neurobiology and Lund Stem Cell Center, BMC A11 and B10, Lund University, S-221 84 Lund, Sweden.; Wellcome-MRC Cambridge Stem Cell Institute and John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Forvie Site, Cambridge CB2 0PY, UK., Jakobsson J; Laboratory of Molecular Neurogenetics, Department of Experimental Medical Science, Wallenberg Neuroscience Center and Lund Stem Cell Center, BMC A11, Lund University, S-221 84 Lund, Sweden.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2022 Sep 14; Vol. 145 (9), pp. 3035-3057.
DOI:	10.1093/brain/awab473
Abstrakt:	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. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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