| Title: |
Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at 16q11.2 and MAPT H1 loci |
| Authors: |
Soutar, MPM; Melandri, D; O'Callaghan, B; Annuario, E; Monaghan, AE; Welsh, NJ; D'Sa, K; Guelfi, S; Zhang, D; Pittman, A; Trabzuni, D; Verboven, AHA; Pan, KS; Kia, DA; Bictash, M; Gandhi, S; Houlden, H; Cookson, MR; Kasri, NN; Wood, NW; Singleton, AB; Hardy, J; Whiting, PJ; Blauwendraat, C; Whitworth, AJ; Manzoni, C; Ryten, M; Lewis, PA; Plun-Favreau, H |
| Publisher Information: |
Oxford University Press |
| Publication Year: |
2022 |
| Collection: |
St George's University of London: Repository |
| Description: |
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 does not exclude a possible association between the MAPT gene and Parkinson's disease, it provides 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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| ISSN: |
1460-2156 |
| Relation: |
https://openaccess.sgul.ac.uk/id/eprint/114834/1/awac325.pdf; Soutar, MPM; Melandri, D; O'Callaghan, B; Annuario, E; Monaghan, AE; Welsh, NJ; D'Sa, K; Guelfi, S; Zhang, D; Pittman, A; et al. Soutar, MPM; Melandri, D; O'Callaghan, B; Annuario, E; Monaghan, AE; Welsh, NJ; D'Sa, K; Guelfi, S; Zhang, D; Pittman, A; Trabzuni, D; Verboven, AHA; Pan, KS; Kia, DA; Bictash, M; Gandhi, S; Houlden, H; Cookson, MR; Kasri, NN; Wood, NW; Singleton, AB; Hardy, J; Whiting, PJ; Blauwendraat, C; Whitworth, AJ; Manzoni, C; Ryten, M; Lewis, PA; Plun-Favreau, H (2022) Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at 16q11.2 and MAPT H1 loci. Brain, 145 (12). pp. 4349-4367. ISSN 1460-2156 https://doi.org/10.1093/brain/awac325 SGUL Authors: Pittman, Alan Michael |
| DOI: |
10.1093/brain/awac325 |
| Availability: |
https://openaccess.sgul.ac.uk/id/eprint/114834/; https://openaccess.sgul.ac.uk/id/eprint/114834/1/awac325.pdf; https://doi.org/10.1093/brain/awac325 |
| Rights: |
cc_by_4 |
| Accession Number: |
edsbas.70157856 |
| Database: |
BASE |