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Mutated ATP10B increases Parkinson's disease risk by compromising lysosomal glucosylceramide export

(2020) ACTA NEUROPATHOLOGICA. 139(6). p.1001-1024
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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
AUTOSOMAL-RECESSIVE PARKINSONISM, PATHOLOGICAL ALPHA-SYNUCLEIN, LEWY, BODIES, GLUCOCEREBROSIDASE MUTATIONS, PHOSPHOLIPASE A(2), LRRK2 G2019S, DEMENTIA, GENE, PREVALENCE, MITOCHONDRIAL, Parkinson's disease, Massive parallel sequencing, ATP10B P-type ATPase, Endo-lysosomal lipid flippase, Loss-of-function, Glucosylceramide

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MLA
Martin, Shaun, et al. “Mutated ATP10B Increases Parkinson’s Disease Risk by Compromising Lysosomal Glucosylceramide Export.” ACTA NEUROPATHOLOGICA, vol. 139, no. 6, 2020, pp. 1001–24, doi:10.1007/s00401-020-02145-7.
APA
Martin, S., Smolders, S., Van den Haute, C., Heeman, B., van Veen, S., Crosiers, D., … BELNEU Consortium, the. (2020). Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export. ACTA NEUROPATHOLOGICA, 139(6), 1001–1024. https://doi.org/10.1007/s00401-020-02145-7
Chicago author-date
Martin, Shaun, Stefanie Smolders, Chris Van den Haute, Bavo Heeman, Sarah van Veen, David Crosiers, Igor Beletchi, et al. 2020. “Mutated ATP10B Increases Parkinson’s Disease Risk by Compromising Lysosomal Glucosylceramide Export.” ACTA NEUROPATHOLOGICA 139 (6): 1001–24. https://doi.org/10.1007/s00401-020-02145-7.
Chicago author-date (all authors)
Martin, Shaun, Stefanie Smolders, Chris Van den Haute, Bavo Heeman, Sarah van Veen, David Crosiers, Igor Beletchi, Aline Verstraeten, Helena Gossye, Geraldine Gelders, Philippe Pals, Norin Nabil Hamouda, Sebastiaan Engelborghs, Jean-Jacques Martin, Jan Eggermont, Peter Paul De Deyn, Patrick Cras, Veerle Baekelandt, Peter Vangheluwe, Christine Van Broeckhoven, Patrick Santens, and the BELNEU Consortium. 2020. “Mutated ATP10B Increases Parkinson’s Disease Risk by Compromising Lysosomal Glucosylceramide Export.” ACTA NEUROPATHOLOGICA 139 (6): 1001–1024. doi:10.1007/s00401-020-02145-7.
Vancouver
1.
Martin S, Smolders S, Van den Haute C, Heeman B, van Veen S, Crosiers D, et al. Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export. ACTA NEUROPATHOLOGICA. 2020;139(6):1001–24.
IEEE
[1]
S. Martin et al., “Mutated ATP10B increases Parkinson’s disease risk by compromising lysosomal glucosylceramide export,” ACTA NEUROPATHOLOGICA, vol. 139, no. 6, pp. 1001–1024, 2020.
@article{8684657,
  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.},
  author       = {Martin, Shaun and Smolders, Stefanie and Van den Haute, Chris and Heeman, Bavo and van Veen, Sarah and Crosiers, David and Beletchi, Igor and Verstraeten, Aline and Gossye, Helena and Gelders, Geraldine and Pals, Philippe and Hamouda, Norin Nabil and Engelborghs, Sebastiaan and Martin, Jean-Jacques and Eggermont, Jan and De Deyn, Peter Paul and Cras, Patrick and Baekelandt, Veerle and Vangheluwe, Peter and Van Broeckhoven, Christine and Santens, Patrick and BELNEU Consortium, the},
  issn         = {0001-6322},
  journal      = {ACTA NEUROPATHOLOGICA},
  keywords     = {AUTOSOMAL-RECESSIVE PARKINSONISM,PATHOLOGICAL ALPHA-SYNUCLEIN,LEWY,BODIES,GLUCOCEREBROSIDASE MUTATIONS,PHOSPHOLIPASE A(2),LRRK2 G2019S,DEMENTIA,GENE,PREVALENCE,MITOCHONDRIAL,Parkinson's disease,Massive parallel sequencing,ATP10B P-type ATPase,Endo-lysosomal lipid flippase,Loss-of-function,Glucosylceramide},
  language     = {eng},
  number       = {6},
  pages        = {1001--1024},
  title        = {Mutated ATP10B increases Parkinson's disease risk by compromising lysosomal glucosylceramide export},
  url          = {http://dx.doi.org/10.1007/s00401-020-02145-7},
  volume       = {139},
  year         = {2020},
}

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