Team Vangheluwe

Study Rationale: Mutations in the genes ATP13A2 (PARK9) and ATP10B trigger Parkinson’s disease (PD) and cause dysfunction of lysosomes, the recycling compartments of the cell. Team Vangheluwe 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.

Hypothesis: Team Vangheluwe hypothesizes 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 α-synuclein toxicity, three major hallmarks of PD.

Study Design: First, Team Vangheluwe will investigate the molecular architecture of polyamine and glucosylceramide transporters and identify mechanisms to modulate their activity. Second, the team 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, they 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, Team Vangheluwe will collect evidence for disturbed polyamine and glucosylceramide transport in PD patients.

Impact on Diagnosis/Treatment of Parkinson’s Disease: Team Vangheluwe will validate the neuroprotective effect of polyamine and glucosylceramide transporters and investigate their potential to reverse α-synuclein and GBA1 pathology. This may offer new therapeutic strategies that correct aberrant lysosomal and mitochondrial dysfunction in Parkinson’s disease. The team will analyze whether alterations in the polyamine and glucosylceramide levels together may be considered as biomarkers for PD.