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P4 ATPases - ATP10B

Parkinson’s disease (PD) is a progressive neurodegenerative brain disease presenting with a variety of motor and non-motor symptoms, loss of midbrain dopaminergic neurons in the substantia nigra pars compacta and the occurrence of α-synucleinpositive Lewy bodies in surviving neurons. Together with the Christine Van Broeckhoven lab we identifed compound heterozygous mutations in the P4 transport ATPase class V type 10B gene (ATP10B) in 3 Early Onset PD patients. Our lab successfully established that ATP10B, previously uncharacterised, encodes a late endo-lysosomal GluCer and phosphatidylcholine (PC) lipid fippase in which patient associated compound heterozygous mutations impair functional activities of ATP10B.


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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