Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at 16q11.2 and MAPT H1 loci
| Autor: | Marc P M Soutar, Daniela Melandri, Benjamin O’Callaghan, Emily Annuario, Amy E Monaghan, Natalie J Welsh, Karishma D’Sa, Sebastian Guelfi, David Zhang, Alan Pittman, Daniah Trabzuni, Anouk H A Verboven, Kylie S Pan, Demis A Kia, Magda Bictash, Sonia Gandhi, Henry Houlden, Mark R Cookson, Nael Nadif Kasri, Nicholas W Wood, Andrew B Singleton, John Hardy, Paul J Whiting, Cornelis Blauwendraat, Alexander J Whitworth, Claudia Manzoni, Mina Ryten, Patrick A Lewis, Hélène Plun-Favreau |
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| Rok vydání: | 2022 |
| Předmět: |
EXPRESSION
Science & Technology KANSL1 IDENTIFICATION MUTATIONS Parkinson's disease PINK1 FOS: Clinical medicine Stem Cells Clinical Neurology Neurosciences Cell Biology UBIQUITIN TAU GENE mitophagy MITOCHONDRIA KAT8 GWAS Neurosciences & Neurology TRANSCRIPTION Neurology (clinical) GENOME-WIDE ASSOCIATION Life Sciences & Biomedicine METAANALYSIS |
| Zdroj: | Brain. 145:4349-4367 |
| ISSN: | 1460-2156 0006-8950 |
| Popis: | 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. ispartof: BRAIN vol:145 issue:12 pages:4349-4367 ispartof: location:England status: published |
| Databáze: | OpenAIRE |
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