52 research outputs found
Mutated ATP10B increases Parkinson's disease risk by compromising lysosomal glucosylceramide export
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
Etude de systèmes quantiques dans les limites semi-classiques et thermodynamique
Doctorat en Sciencesinfo:eu-repo/semantics/nonPublishe
Two-dimensional quantum spin Hamiltonians: Spectral properties
info:eu-repo/semantics/publishe
Two-dimensional quantum spin hamiltonian: Spectral and dynamical domplexities
info:eu-repo/semantics/publishe
Vibrational time recurrences in a model of acetylene 12C2H2
info:eu-repo/semantics/publishe
The semiclassical regime of intramolecular vibrational dynamics
info:eu-repo/semantics/publishe
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