Mutations in the genes ATP13A2 (PARK9) and ATP10B trigger Parkinson’s disease (PD) and cause dysfunction of lysosomes, the recycling compartments of the cell. We explained these defects by impaired transport of polyamines and glucosylceramide out of the lysosome, respectively. Polyamines are cell protective agents, whereas the levels of the lipid glucosylceramide are controlled by GBA1, the major genetic risk factor of PD. However, there is a clear knowledge gap regarding the biology of polyamine and glucosylceramide transport systems in neurons and their supporting cells of the brain, and how an impaired polyamine and glucosylceramide distribution in these cells leads to neurodegeneration.
We hypothesize that an impaired polyamine and glucosylceramide transport activity causes toxic accumulation of these substances in lysosomes and leads to a shortage elsewhere in the cell. Together, this may cause lysosomal and mitochondrial dysfunction, and lead to alpha-synuclein toxicity, three major hallmarks of PD.
First, we will investigate the molecular architecture of polyamine and glucosylceramide transporters and identify mechanisms to modulate their activity. Second, we will examine how these transporters influence the intracellular distribution of polyamine and glucosylceramide, and how this affects the cross-talk between lysosomes and mitochondria. Third, we will investigate how dysfunctional polyamine and glucosylceramide transporters affect other PD pathways, such as mitophagy, GBA1 and alpha-synuclein aggregation, and whether the modulation of these transporters can be validated as therapeutic approach for PD. Finally, we will collect evidence for disturbed polyamine and glucosylceramide transport in PD patients.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
We will validate the neuroprotective effect of polyamine and glucosylceramide transporters and investigate their potential to reverse alpha-synuclein and GBA1 pathology. This may offer new therapeutic strategies that correct aberrant lysosomal and mitochondrial dysfunction in Parkinson’s disease. We will analyze whether alterations in the polyamine and glucosylceramide levels together may be considered as biomarkers for PD.