Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson's disease at 16q11.2 and MAPT H1 loci.
journal contributionposted on 2022-12-21, 10:43 authored by Marc PM 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 HA 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
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.