Study Rationale: Mutations in the genes ATP13A2, GBA1 and ATP10B trigger Parkinson’s disease (PD) and cause dysfunction of lysosomes, the recycling compartments of the cell. These genes regulate the lysosome’s ability to maintain lipid and polyamine homeostasis. However, whether these genes are in some way interconnected, and whether they function differently in neurons and in non-neuronal brain cells, remains unknown.
Hypothesis: We hypothesize that polyamine and lipid homeostasis in lysosomes are interconnected in a cell-type specific manner, which may influence other PD-relevant pathways.
Study Design: Our consortium has access to purified protein, stem cells, brain organoids and preclinical models to investigate the consequences of loss of ATP13A2, ATP10B and GBA1 on lysosomal homeostasis. We will identify mechanisms of ATP13A2 and ATP10B regulation and dissect how lysosomal polyamine and lipid pathways intersect. We will also explore cell-type-specific mechanisms of lysosomal and polyamine dysregulation, and we will examine the molecular mechanisms that determine whether individuals with GBA1 develop signs of PD.
Impact on Diagnosis/Treatment of Parkinson’s disease: Establishing connections between ATP13A2, ATP10B and GBA1 will reveal the central mechanisms of lysosomal impairment in PD and may highlight pathways that can be targeted therapeutically, opening the door for future polyamine-modulating therapies in PD. Identification of GBA1-dependent PD risk modifiers will offer insights into disease mechanisms and offer therapeutic strategies.
Next Steps for Development: If successful, the study will aid ongoing small-molecule drug discovery efforts aimed at restoring lysosomal function in PD. Comparing the impact of polyamine treatments will guide the design of future polyamine modulation strategies in various PD forms, which will be evaluated first in a clinical-trial ready cohort of ATP13A2 carriers.