ATP13A2, also known as PARK9, is a late endolysosomal transporter. It functions in polyamine transport, with a high affinity for spermine [1]. It promotes cellular polyamine uptake via endocytosis and exports polyamines from lysosomes to the cytosol [1]. ATP13A2 is genetically associated with a spectrum of neurodegenerative disorders, such as Kufor-Rakeb syndrome and early-onset Parkinson's disease [1,2].

Loss-of-function mutations in ATP13A2 lead to lysosomal polyamine accumulation, rupture, and subsequent cell death [1,3]. In neurons and nematodes with impaired ATP13A2 expression, this phenotype is recapitulated, highlighting defective lysosomal polyamine export as a mechanism for lysosome-dependent cell death in neurodegeneration [1]. In SH-SY5Y cells and patient-derived fibroblasts, ATP13A2 deficiency exacerbates rotenone-induced mitochondrial-generated superoxide, disturbing mitochondrial functionality and causing toxicity and cell death [3].

In conclusion, ATP13A2 is crucial for lysosomal polyamine export, which is essential for maintaining cell viability. Its deficiency-related phenotypes in model organisms like neurons and nematodes contribute to our understanding of neurodegenerative diseases associated with ATP13A2 mutations. The role of ATP13A2 in countering mitochondrial oxidative stress further emphasizes its importance in cellular homeostasis and neurodegenerative disease mechanisms [1,3].

References:

1. van Veen, Sarah, Martin, Shaun, Van den Haute, Chris, Eggermont, Jan, Vangheluwe, Peter. 2020. ATP13A2 deficiency disrupts lysosomal polyamine export. In Nature, 578, 419-424. doi:10.1038/s41586-020-1968-7. https://pubmed.ncbi.nlm.nih.gov/31996848/

2. Croucher, Kristina M, Fleming, Sheila M. 2024. ATP13A2 (PARK9) and basal ganglia function. In Frontiers in neurology, 14, 1252400. doi:10.3389/fneur.2023.1252400. https://pubmed.ncbi.nlm.nih.gov/38249738/

3. Vrijsen, Stephanie, Besora-Casals, Laura, van Veen, Sarah, Martin, Shaun, Vangheluwe, Peter. 2020. ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress. In Proceedings of the National Academy of Sciences of the United States of America, 117, 31198-31207. doi:10.1073/pnas.1922342117. https://pubmed.ncbi.nlm.nih.gov/33229544/