ArticleActa neuropathologica2020
Mutated ATP10B increases Parkinson's disease risk by compromising lysosomal glucosylceramide export.
Article in Acta neuropathologica, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 63 citations in OpenAlex.
- Fluorescence-Gated Flow Cytometry Approach for Measuring Lipid Flippase Activity in Mammalian Cells.The Journal of membrane biology · 2026Article
- Repairing Atp10D in C57Bl/6J mice restores protein expression but does not mitigate metabolic stress from high fat diet.Scientific reports · 2026Article
- Modest improvement of metabolic and behavioral deficits with long-term ambroxol treatment in a Pink1Acta pharmacologica Sinica · 2026Article
- The emerging landscape of brain glycosylation: from molecular complexity to therapeutic potential.Experimental & molecular medicine · 2025Review
- Elevated hexosylceramides in Parkinson's disease cause gene upregulations in neurons mimicking responses to pathogens.NPJ Parkinson's disease · 2025Article
- Lipid flippases ATP9A and ATP9B form a complex and contribute to the exocytic pathway from the Golgi.Life science alliance · 2025Article
- Substrates, regulation, cellular functions, and disease associations of P4-ATPases.Communications biology · 2025Review
- Article
- Lysosomal dysfunction in α-synuclein pathology: molecular mechanisms and therapeutic strategies.Cellular and molecular life sciences : CMLS · 2024Review
- Functional and in silico analysis of ATP8A2 and other P4-ATPase variants associated with human genetic diseases.Disease models & mechanisms · 2024Article
- Common genetic risk for Parkinson's disease and dysfunction of the endo-lysosomal system.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- Flipping the script: Advances in understanding how and why P4-ATPases flip lipid across membranes.Biochimica et biophysica acta. Molecular cell research · 2024Review
- Glucosylceramide flippases contribute to cellular glucosylceramide homeostasis.Journal of lipid research · 2024Article
- Article
- ATP10A deficiency results in male-specific infertility in mice.Frontiers in cell and developmental biology · 2024Article
- Large-scale rare variant burden testing in Parkinson's disease.Brain : a journal of neurology · 2023Article
- Recent advances in novel mutation genes of Parkinson's disease.Journal of neurology · 2023Review
- Regulation of phospholipid distribution in the lipid bilayer by flippases and scramblases.Nature reviews. Molecular cell biology · 2023Review
- Defective lysosomal acidification: a new prognostic marker and therapeutic target for neurodegenerative diseases.Translational neurodegeneration · 2023Review
- Review
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21 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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 α-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.
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