PD Functional Genomics | 2020
IMPACT-PD – Implications of Polyamine and Glucosylceramide Transport in Parkinson’s Disease
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.
By dissecting the neuroprotective effect of lysosomal polyamine and glucosylceramide transporters at the molecular level, Team Vangheluwe will establish new pathways implicated in Parkinson’s disease that may serve as novel therapeutic targets to restore lysosomal dysfunction in Parkinson’s disease. View Team Outcomes.
Here is an overview of how this team’s article findings have contributed to the PD field as of November 2023. There are two different categorizations of these contributions – one by impact to the PD community and a second by scientific theme.
Below is an example of a research output from the team that contributes to the ASAP mission of accelerating discoveries for PD.
Mutations in ATP13A2 cause a variety of neurodegenerative disorders characterized by dysfunctional lysosomes and mitochondria as well as increased oxidative stress. ATP13A2 is a lysosomal polyamine exporter that controls cellular polyamine levels. Polyamines are vital for eukaryotic cells, as they are potent anti-oxidants, anti-inflammatory agents, and chaperones and they are known to regulate translation and autophagy. When ATP13A2 doesn’t work properly, polyamines accumulate in lysosomes, causing lysosomal dysfunction and rupture. Reports also highlight a mitochondrial protective effect of ATP13A2, but the underlying molecular mechanism remained unknown. Team Vangheluwe shows that the polyamines transported by ATP13A2 reduce oxidative stress generated by mitochondria, thereby preventing the initiation of a stress response and cell death. The combined effects of ATP13A2 on lysosomal health and mitochondrial oxidative stress help explain the neuroprotective effects of ATP13A2.