期刊
BRAIN
卷 145, 期 12, 页码 4349-4367出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awac325
关键词
GWAS; KANSL1; KAT8; mitophagy; Parkinson's disease
资金
- UK Medical Research Council (MRC) [MR/M02492X/1]
- High-Content Biology Platform at the MRC-UCL LMCB university unit [MC_U12266B]
- MRC MBU [MC_UU_00015/6]
- UCL Translational Research Office administered seed funds
- MRC [MR/N026004/1]
- MRC CASE studentship [MR/P016677/1]
- Michael J. Fox Foundation for Parkinson's Research [MJFF-010437]
- Alzheimer's Research UK (ARUK) [ARUK-2018DDI-UCL]
- UK MRC through the award of Tenure-track Clinician Scientist Fellowship [MR/N008324/1]
- Aligning Science Across Parkinson [ASAP 000478]
- Intramural Research Programs of the National Institute on Aging (NIA)
- NIHR BRC
Parkinson's disease is a common and incurable neurodegenerative disease. Genetic variants identified through genome-wide association studies have advanced our understanding of the disease's genetic risk. This study found that KANSL1 and KAT8 are regulators of PINK1-dependent mitophagy and may contribute to idiopathic Parkinson's disease.
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. Soutar et al. show that two Parkinson's disease candidate genes, KANSL1 and KAT8, are regulators of PINK1-dependent mitophagy in neurons. The findings suggest that impairments in PINK1-mediated mitochondrial quality control may be a contributing factor to idiopathic Parkinson's disease.
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