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

Soutar, M.; Melandri, D.; Annuario, E.; Monaghan, A.; Welsh, N.; D'Sa, K.; Guelfi, S.; Zhang, D.; Pittman, A.; Trabzuni, D.; Pan, K.; Kia, D. A.; Bictash, M.; Gandhi, S.; Houlden, H.; Cookson, M. R.; Wood, N.; Singleton, A.; Hardy, J.; Whiting, P.; Blauwendraat, C.; Whitworth, A.; Manzoni, C.; Ryten, M.; Lewis, P.; Plun-Favreau, H.

doi:10.1101/2020.01.06.896241

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bioRxiv · 10.1101/2020.01.06.896241

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

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Abstract

Parkinsons 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. We show that KAT8 and KANSL1 modulate PINK1 gene expression and subsequent PINK1-mitophagy. These findings suggest PINK1-mitophagy is a contributing factor to idiopathic PD. 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 PD, 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.

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Soutar, M., Melandri, D., Annuario, E., Monaghan, A., Welsh, N., D'Sa, K., Guelfi, S., Zhang, D., Pittman, A., Trabzuni, D., Pan, K., Kia, D. A., Bictash, M., Gandhi, S., Houlden, H., Cookson, M. R., Wood, N., Singleton, A., Hardy, J., Whiting, P., Blauwendraat, C., Whitworth, A., Manzoni, C., Ryten, M., Lewis, P., Plun-Favreau, H.. 2020-01-07. Regulation of mitophagy by the NSL complex underlies genetic risk for Parkinson's disease at Chr16q11.2 and on the MAPT H1 allele.. https://doi.org/10.1101/2020.01.06.896241

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