Protein aggregation and calcium dysregulation are hallmarks of familial Parkinson's disease in midbrain dopaminergic neurons.

Autor:	Virdi GS; The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA., Choi ML; The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA., Evans JR; The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA., Yao Z; The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK., Athauda D; The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK., Strohbuecker S; The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK., Nirujogi RS; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.; Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK., Wernick AI; The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK.; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA., Pelegrina-Hidalgo N; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ, UK.; Center for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK., Leighton C; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ, UK.; Center for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK., Saleeb RS; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ, UK., Kopach O; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK., Alrashidi H; UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK., Melandri D; Department of Neurodegenerative Diseases, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK., Perez-Lloret J; The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK., Angelova PR; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK., Sylantyev S; Rowett Institute, University of Aberdeen, Ashgrove Rd West, Aberdeen, AB25 2ZD, UK., Eaton S; UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK., Heales S; UCL Great Ormond Street Institute of Child Health, London, WC1N 1EH, UK., Rusakov DA; Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG, UK., Alessi DR; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.; Medical Research Council (MRC) Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dow Street, Dundee, DD1 5EH, UK., Kunath T; Center for Regenerative Medicine, University of Edinburgh, Edinburgh, EH16 4UU, UK., Horrocks MH; EaStCHEM School of Chemistry, University of Edinburgh, Edinburgh, EH9 3FJ, UK., Abramov AY; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK., Patani R; The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK. rickie.patani@crick.ac.uk.; Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK. rickie.patani@crick.ac.uk., Gandhi S; The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK. sonia.gandhi@crick.ac.uk.; Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, Queen Square, London, WC1N 3BG, UK. sonia.gandhi@crick.ac.uk.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA. sonia.gandhi@crick.ac.uk.
Jazyk:	angličtina
Zdroj:	NPJ Parkinson's disease [NPJ Parkinsons Dis] 2022 Nov 24; Vol. 8 (1), pp. 162. Date of Electronic Publication: 2022 Nov 24.
DOI:	10.1038/s41531-022-00423-7
Abstrakt:	Mutations in the SNCA gene cause autosomal dominant Parkinson's disease (PD), with loss of dopaminergic neurons in the substantia nigra, and aggregation of α-synuclein. The sequence of molecular events that proceed from an SNCA mutation during development, to end-stage pathology is unknown. Utilising human-induced pluripotent stem cells (hiPSCs), we resolved the temporal sequence of SNCA-induced pathophysiological events in order to discover early, and likely causative, events. Our small molecule-based protocol generates highly enriched midbrain dopaminergic (mDA) neurons: molecular identity was confirmed using single-cell RNA sequencing and proteomics, and functional identity was established through dopamine synthesis, and measures of electrophysiological activity. At the earliest stage of differentiation, prior to maturation to mDA neurons, we demonstrate the formation of small β-sheet-rich oligomeric aggregates, in SNCA-mutant cultures. Aggregation persists and progresses, ultimately resulting in the accumulation of phosphorylated α-synuclein aggregates. Impaired intracellular calcium signalling, increased basal calcium, and impairments in mitochondrial calcium handling occurred early at day 34-41 post differentiation. Once midbrain identity fully developed, at day 48-62 post differentiation, SNCA-mutant neurons exhibited mitochondrial dysfunction, oxidative stress, lysosomal swelling and increased autophagy. Ultimately these multiple cellular stresses lead to abnormal excitability, altered neuronal activity, and cell death. Our differentiation paradigm generates an efficient model for studying disease mechanisms in PD and highlights that protein misfolding to generate intraneuronal oligomers is one of the earliest critical events driving disease in human neurons, rather than a late-stage hallmark of the disease. (© 2022. The Author(s).)
Databáze:	MEDLINE
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