Onderzoek naar de rol van de lysosomale P-type ATPase ATP10B in preklinische modellen voor de ziekte van Parkinson

ATP10B is a lysosomal P-type adenosine triphosphatase (ATPase) known for translocating glucosylceramide (GluCer) and phosphatidylcholine (PC) from the inside to the outside of the lysosomal membrane. Compound heterozygous mutations affecting ATP10B protein activity have been identified in a small subset of patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Several genetic studies have since explored whether mutations in the ATP10B gene follow a recessive inheritance pattern or contribute to an increased PD risk. However, the findings have been inconclusive and sometimes conflicting. In idiopathic PD, ATP10B messenger RNA (mRNA) levels have been reported to decrease in the substantia nigra (SN) and the medulla oblongata. Interestingly, in vitro studies have demonstrated that reduced ATP10B protein levels cause lysosomal dysfunction and increase neuronal vulnerability, supporting a potential pathogenic role in PD. Mutations in several lysosomal genes have already been linked to PD pathology, and their disruption in in vivo models often leads to dopaminergic neuron loss, α-synuclein aggregation, and motor deficits. In parallel, altered lipid profiles, particularly involving GluCer and related sphingolipids, have been observed in PD patients, highlighting the contribution of lipid dysregulation to disease progression. Given that ATP10B is a lysosomal protein involved in lipid transport, its loss of function may contribute to PD pathology through similar mechanisms, linking lysosomal impairment and lipid imbalance to neurodegeneration.