A defect in the ATP13A2 gene causes cell death by disrupting the cellular transport of polyamines, scientists at KU Leuven have discovered. When this happens in the part of the brain that controls body movement, it can lead to Parkinson’s disease.
“We found that ATP13A2 transports polyamines and is crucial for their uptake into the cell. Polyamines are essential molecules that support many cell functions and protect cells in stress conditions. But how polyamines are taken up and transported in human cells was still a mystery. Our study reveals that ATP13A2 plays a vital role in that process,”
explains Peter Vangheluwe from the Laboratory of Cellular Transport Systems at KU Leuven and senior author of the paper.
Lysosomal Polyamine Export
Parkinson’s disease is one of the most common neurodegenerative disorders, afflicting more than 6 million patients around the world. Around 20 genetic defects have already been linked to the disease, but researchers don’t understand function of many of these genes.
“We found that ATP13A2 transports polyamines and is crucial for their uptake into the cell. Polyamines are essential molecules that support many cell functions and protect cells in stress conditions. But how polyamines are taken up and transported in human cells was still a mystery. Our study reveals that ATP13A2 plays a vital role in that process. Our experiments showed that polyamines enter the cell via lysosomes and that ATP13A2 transfers polyamines from the lysosome to the cell interior. This transport process is essential for lysosomes to function properly as the ‘waste disposal system’ of the cell, where obsolete cell material is broken down and recycled.
However, mutations in the ATP13A2 gene disrupt this transport process, so that polyamines build up in lysosomes. As a result, the lysosomes swell and eventually burst, causing the cells to die. When this happens in the part of the brain that controls body movement, this process may trigger the motion problems and tremors related to Parkinson’s disease,”
Important Step Forward
Unravelling the role of ATP13A2 is an important step forward in Parkinson’s research and sheds new light on what causes the disease, but a lot of work remains to be done.
“We now have to investigate how deficient polyamine transport is linked to other defects in Parkinson’s disease such as the accumulation of plaques in the brain and malfunctioning of the mitochondria, the ‘energy factories’ of the cell. We need to examine how these mechanisms influence each other,”
professor Peter Vangheluwe says.
“The discovery of the polyamine transport system in animals has implications beyond Parkinson’s disease as well, because polyamine transporters also play a role in other age-related conditions, including cancer, cardiovascular diseases, and several neurological disorders,”
he adds. van Veen, S., Martin, S., Van den Haute, C. et al. ATP13A2 deficiency disrupts lysosomal polyamine export. Nature (2020). https://doi.org/10.1038/s41586-020-1968-7
Image: Vall d’Hebron Institut de Recerca VHIR/Flickr. Endogenous alpha-synuclein protein levels in a coronal brain section of a monkey intrastriatally inoculated with purified nigral Lewy body extracts derived from Parkinson disease’s post-mortem brains