Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson's disease at 16q11.2 and MAPT H1 loci.

Autor:	Soutar MPM; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK., Melandri D; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK., O'Callaghan B; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA., Annuario E; Department of Basic and Clinical Neuroscience, King's College, London, UK., Monaghan AE; UCL Alzheimer's Research UK, Drug Discovery Institute, London, UK.; UCL Dementia Research Institute, London, UK., Welsh NJ; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK., D'Sa K; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.; Francis Crick Institute, London, UK., Guelfi S; NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK., Zhang D; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA., Pittman A; Genetics Research Centre, Molecular and Clinical Sciences, St Georges University, London, UK., Trabzuni D; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK., Verboven AHA; Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, 6500 HB Nijmegen, The Netherlands.; Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, 6500 HB Nijmegen, The Netherlands., Pan KS; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK., Kia DA; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.; Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK., Bictash M; UCL Alzheimer's Research UK, Drug Discovery Institute, London, UK.; UCL Dementia Research Institute, London, UK., Gandhi S; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.; Francis Crick Institute, London, UK.; Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK., Houlden H; Department of Neuromuscular Disease, UCL Queen Square Institute of Neurology, London, UK., Cookson MR; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA., Kasri NN; Department of Human Genetics, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, 6500 HB Nijmegen, The Netherlands.; Department of Cognitive Neuroscience, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, 6500 HB Nijmegen, The Netherlands., Wood NW; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.; Department of Clinical and Movement Neuroscience, UCL Queen Square Institute of Neurology, London, UK., Singleton AB; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Hardy J; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.; UCL Dementia Research Institute, London, UK., Whiting PJ; UCL Alzheimer's Research UK, Drug Discovery Institute, London, UK.; UCL Dementia Research Institute, London, UK., Blauwendraat C; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.; Center for Alzheimer's and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA., Whitworth AJ; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, UK., Manzoni C; Department of Pharmacology, UCL School of Pharmacy, London, UK., Ryten M; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.; NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK.; Department of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK., Lewis PA; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.; Department of Comparative Biomedical Sciences, Royal Veterinary College, LondonUK., Plun-Favreau H; Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK.; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA.
Jazyk:	angličtina
Zdroj:	Brain : a journal of neurology [Brain] 2022 Dec 19; Vol. 145 (12), pp. 4349-4367.
DOI:	10.1093/brain/awac325
Abstrakt:	Parkinson's disease is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies has considerably advanced our understanding of the Parkinson's disease genetic risk. Understanding the functional significance of the risk loci is now a critical step towards translating these genetic advances into an enhanced biological understanding of the disease. Impaired mitophagy is a key causative pathway in familial Parkinson's disease, but its relevance to idiopathic Parkinson's disease is unclear. We used a mitophagy screening assay to evaluate the functional significance of risk genes identified through genome-wide association studies. We identified two new regulators of PINK1-dependent mitophagy initiation, KAT8 and KANSL1, previously shown to modulate lysine acetylation. These findings suggest PINK1-mitophagy is a contributing factor to idiopathic Parkinson's disease. KANSL1 is located on chromosome 17q21 where the risk associated gene has long been considered to be MAPT. While our data do not exclude a possible association between the MAPT gene and Parkinson's disease, they provide strong evidence that KANSL1 plays a crucial role in the disease. Finally, these results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration. (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)
Databáze:	MEDLINE
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