P4 ATPases - ATP10B
ATP10B, a previously uncharacterized member of the P4-type ATPase family, encodes a late endo-lysosomal lipid flippase for glucosylceramide (GluCer) and phosphatidylcholine (PC). Our lab demonstrated that patient-associated compound heterozygous mutations in ATP10B impair its functional activity. In collaboration with the Van Broeckhoven lab (VIB, University of Antwerp), we identified these mutations in three early-onset Parkinson’s disease patients, linking ATP10B dysfunction to disease pathology.
Team
Therapeutic area: Parkinson's disease
Highlights of our work
Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export
MARCH 2020, Acta Neuropathologica
Our collaborators in Antwerp performed whole exome sequencing in 52 early-onset PD patients and identifed 3 carriers of compound heterozygous mutations in the ATP10B P4-type ATPase gene. Genetic screening of a Belgian PD and dementia with Lewy bodies (DLB) cohort identifed 4 additional compound heterozygous mutation carriers. Shaun established that ATP10B encodes a late endo-lysosomal lipid fippase that translocates the lipids glucosylceramide (GluCer) and phosphatidylcholine (PC) towards the cytosolic membrane leaflet. The PD associated ATP10B mutants are catalytically inactive and fail to provide cellular protection against the environmental PD risk factors rotenone and manganese. In isolated cortical neurons, loss of ATP10B leads to general lysosomal dysfunction and cell death. Impaired lysosomal functionality and integrity is well known to be implicated in PD pathology and linked to multiple causal PD genes and genetic risk factors. Our results indicate that recessive loss of function mutations in ATP10B increase risk for PD by disturbed lysosomal export of GluCer and PC. Both ATP10B and glucocerebrosidase 1, encoded by the PD risk gene GBA1, reduce lysosomal GluCer levels, emerging lysosomal GluCer accumulation as a potential PD driver.
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