Mutated ATP10B increases Parkinson's disease risk by compromising lysosomal glucosylceramide export
Open Access
- 13 March 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Acta Neuropathologica
- Vol. 139 (6), 1001-1024
- https://doi.org/10.1007/s00401-020-02145-7
Abstract
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 alpha-synuclein-positive Lewy bodies in surviving neurons. Here, we performed whole exome sequencing in 52 early-onset PD patients and identified 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 identified 4 additional compound heterozygous mutation carriers (6/617 PD patients, 0.97%; 1/226 DLB patients, 0.44%). We established that ATP10B encodes a late endo-lysosomal lipid flippase 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.Keywords
Funding Information
- Flemish government initiated Methusalem excellence program, Belgium
- Flanders Impulse Program on Networks for Dementia Research, Belgium
- research foundation flanders, belgium
- University of Antwerp Research Fund, Belgiu
- KU Leuven (C16/15/073, LysoCaN, OT/14/120, IOF C32/15/031)
- Research Foundation Flanders (S006617N SBO Neuro-Traffic, S006617N SBO Neuro-Traffic)
- Michael J. Fox Foundation and the Queen Elisabeth Medical Foundation for Neurosciences
- Ernest Solvay Award
- Research Foundation Flanders PhD fellowship (11Y7518N)
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