Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at Chr16q11.2 and on the MAPT H1 allele

Soutar, MPM and Melandri, D and Annuario, E and Monaghan, AE and Welsh, NJ and D’Sa, K and Guelfi, S and Zhang, D and Pittman, A and Trabzuni, D and Pan, KS and Kia, DA and Bictash, M and Gandhi, S and Houlden, H and Cookson, MR and Wood, NW and Singleton, AB and Hardy, J and Whiting, PJ and Blauwendraat, C and Whitworth, AJ and Manzoni, C and Ryten, M and Lewis, PA and Plun-Favreau, H (2020) Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson’s disease at Chr16q11.2 and on the MAPT H1 allele. Cold Spring Harbor Laboratory. (Submitted)

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Official URL: https://doi.org/10.1101/2020.01.06.896241

Abstract

Parkinson’s disease (PD) is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies (GWAS) has considerably advanced our understanding of the PD 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 PD, but its relevance to idiopathic PD is unclear. We used a mitophagy screening assay to evaluate the functional significance of risk genes identified through GWAS. We identified two new regulators of PINK1-mitophagy, KAT8 and KANSL1, previously shown to modulate lysine acetylation. These findings establish PINK1-mitophagy as a contributing factor to idiopathic PD. KANSL1 is located on chromosome 17q21 where the risk associated gene has long been considered to be MAPT. Our data provide evidence that this assignment is likely to be incorrect and that variability at KANSL1 underpins this association. Finally, these results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration.

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