2. Academic Validation
  3. Mutated ATP10B increases Parkinson's disease risk by compromising lysosomal glucosylceramide export

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

  • Acta Neuropathol. 2020 Jun;139(6):1001-1024. doi: 10.1007/s00401-020-02145-7.
Shaun Martin # 1,  Stefanie Smolders # 2 3 4,  Chris Van den Haute 5 6,  Bavo Heeman 2 3 4,  Sarah van Veen 1,  David Crosiers 2 3 7,  Igor Beletchi 1,  Aline Verstraeten 2 3 4,  Helena Gossye 2 3 4 7 8,  Géraldine Gelders 5,  Philippe Pals 3 7,  Norin Nabil Hamouda 1,  Sebastiaan Engelborghs 3 8,  Jean-Jacques Martin 3,  Jan Eggermont 1,  Peter Paul De Deyn 3 8,  Patrick Cras 3 7,  Veerle Baekelandt 5 6,  Peter Vangheluwe # 9,  Christine Van Broeckhoven # 10 11 12,  BELNEU consortium
Affiliations

Affiliations

  • 1 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.
  • 2 Center for Molecular Neurology, VIB, University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium.
  • 3 Institute Born-Bunge, Antwerp, Belgium.
  • 4 University of Antwerp, Antwerp, Belgium.
  • 5 Laboratory for Neurobiology and Gene Therapy, KU Leuven, Leuven, Belgium.
  • 6 Leuven Viral Vector Core, KU Leuven, Leuven, Belgium.
  • 7 Department of Neurology, Antwerp University Hospital, Edegem, Belgium.
  • 8 Department of Neurology and Memory Clinic, Antwerp Hospital Network, General Hospitals Middelheim and Hoge Beuken, Antwerp, Belgium.
  • 9 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.
  • 10 Center for Molecular Neurology, VIB, University of Antwerp, Universiteitsplein 1, 2610, Antwerpen, Belgium. christine.vanbroeckhoven@uantwerpen.vib.be.
  • 11 Institute Born-Bunge, Antwerp, Belgium. christine.vanbroeckhoven@uantwerpen.vib.be.
  • 12 University of Antwerp, Antwerp, Belgium. christine.vanbroeckhoven@uantwerpen.vib.be.
  • # Contributed equally.
PMID: 32172343 DOI: 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 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.

Keywords

ATP10B P-type ATPase; Endo-lysosomal lipid flippase; Glucosylceramide; Loss-of-function; Massive parallel sequencing; Parkinson’s disease.

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