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

Autor: Martin S; Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven Campus Gasthuisberg, O&N I Herestraat 49-bus 802, 3000, Leuven, Belgium., Smolders S; Center for Molecular Neurology, VIB, University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium.; Institute Born-Bunge, Antwerp, Belgium.; University of Antwerp, Antwerp, Belgium., Van den Haute C; Laboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, Belgium.; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium., Heeman B; Center for Molecular Neurology, VIB, University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium.; Institute Born-Bunge, Antwerp, Belgium.; University of Antwerp, Antwerp, Belgium., van Veen S; Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven Campus Gasthuisberg, O&N I Herestraat 49-bus 802, 3000, Leuven, Belgium., Crosiers D; Center for Molecular Neurology, VIB, University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium.; Institute Born-Bunge, Antwerp, Belgium.; Department of Neurology, Antwerp University Hospital, Edegem, Belgium., Beletchi I; Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven Campus Gasthuisberg, O&N I Herestraat 49-bus 802, 3000, Leuven, Belgium., Verstraeten A; Center for Molecular Neurology, VIB, University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium.; Institute Born-Bunge, Antwerp, Belgium.; University of Antwerp, Antwerp, Belgium., Gossye H; Center for Molecular Neurology, VIB, University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium.; Institute Born-Bunge, Antwerp, Belgium.; University of Antwerp, Antwerp, Belgium.; Department of Neurology, Antwerp University Hospital, Edegem, Belgium.; Department of Neurology and Memory Clinic, Antwerp Hospital Network, General Hospitals Middelheim and Hoge Beuken, Antwerp, Belgium., Gelders G; Laboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, Belgium., Pals P; Institute Born-Bunge, Antwerp, Belgium.; Department of Neurology, Antwerp University Hospital, Edegem, Belgium., Hamouda NN; Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven Campus Gasthuisberg, O&N I Herestraat 49-bus 802, 3000, Leuven, Belgium., Engelborghs S; Institute Born-Bunge, Antwerp, Belgium.; Department of Neurology and Memory Clinic, Antwerp Hospital Network, General Hospitals Middelheim and Hoge Beuken, Antwerp, Belgium., Martin JJ; Institute Born-Bunge, Antwerp, Belgium., Eggermont J; Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven Campus Gasthuisberg, O&N I Herestraat 49-bus 802, 3000, Leuven, Belgium., De Deyn PP; Institute Born-Bunge, Antwerp, Belgium.; Department of Neurology and Memory Clinic, Antwerp Hospital Network, General Hospitals Middelheim and Hoge Beuken, Antwerp, Belgium., Cras P; Institute Born-Bunge, Antwerp, Belgium.; Department of Neurology, Antwerp University Hospital, Edegem, Belgium., Baekelandt V; Laboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, Belgium.; Leuven Viral Vector Core, KU Leuven, Leuven, Belgium., Vangheluwe P; Laboratory of Cellular Transport Systems, Department of Cellular and Molecular Medicine, KU Leuven Campus Gasthuisberg, O&N I Herestraat 49-bus 802, 3000, Leuven, Belgium. peter.vangheluwe@kuleuven.be., Van Broeckhoven C; Center for Molecular Neurology, VIB, University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium. christine.vanbroeckhoven@uantwerpen.vib.be.; Institute Born-Bunge, Antwerp, Belgium. christine.vanbroeckhoven@uantwerpen.vib.be.; University of Antwerp, Antwerp, Belgium. christine.vanbroeckhoven@uantwerpen.vib.be.
Jazyk: angličtina
Zdroj: Acta neuropathologica [Acta Neuropathol] 2020 Jun; Vol. 139 (6), pp. 1001-1024. Date of Electronic Publication: 2020 Mar 14.
DOI: 10.1007/s00401-020-02145-7
Abstrakt: 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.
Databáze: MEDLINE
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