Modulating polyamines and polyamine transport in Parkinson’s disease

Parkinson’s disease is one of the most frequent neurodegenerative diseases. While the root cause and molecular mechanisms underlying Parkinson’s disease remain incompletely understood, lysosomes are critically disturbed, which contributes to the accumulation of misfolded proteins and defective mitochondria. Our lab is specialized in the study of endo-/lysosomal polyamine transporters, such as ATP13A2, which has been genetically linked with Parkinson’s disease (PARK9 locus). Our research revealed that ATP13A2 transports polyamines out of the lysosome, contributing to lysosomal and mitochondrial health. The M.J. Fox Foundation has prioritized ATP13A2 as a new target for Parkinson’s disease, and our molecular insights into the regulation of ATP13A2 have offered new therapeutic strategies, which we actively pursue. Our work in the Aligning Science Across Parkinson’s program demonstrated that a disturbed polyamine homeostasis affects Parkinson’s disease symptoms and that polyamines modulate Parkinson’s disease pathways. Using preclinical mouse models we evaluate the potential of polyamine modulation strategies to rescue the consequences of ATP13A2 deficiency, and are assembling a patient cohort with ATP13A2 carriers. Finally, we study the interconnections between ATP13A2 and closely related polyamine transporters ATP13A3 and ATP13A4, which remain virtually unexplored but are emerging as new drug targets.