P5 ATPases - Discovery of the mammalian polyamine transporters
Phylogenetic analysis of P-type ATPase sequences in early genomic sequences revealed the existence of a fifth P-type ATPase subfamily, which is exclusively found in eukaryotic lineages. However, the substrate specificity and exact cellular role of the P5-type ATPases remained elusive for a long time. Several of the five human P5 ATPases have attracted considerable interest as they are implicated in human disorders.
Pioneering work of our lab successfully revealed the molecular identity of ATP13A2, a P5B-ATPase, as the first identified mammalian polyamine transporter. ATP13A2 is genetically implicated in a spectrum of neurodegenerative disorders such as Kufor-Rakeb syndrome, early-onset Parkinson’s disease (PD) but also NCL and ALS. Importantly, our work demonstrates that defective lysosomal polyamine export represents a novel pathway in the molecular pathogenesis of lysosome-dependent cell death in neurodegeneration.
LCTS currently has several follow-up projects running on ATP13A2, including a drug discovery program. Other P5B-ATPase isoforms are also under study, such as ATP13A3 in pulmonary arterial hypertension and ATP13A4 in neurodevelopment disorders.
Dr. Shaun Martin
Dr. Veronick Benoy
Dr. Sarah Van Veen
Highlights of our work
Deficient lysosomal polyamine export is at the heart of ATP13A2-associated neurodegeneration
During her work as a Ph.D. student, Sarah established ATP13A2 as a lysosomal polyamine exporter with the highest affinity for spermine. Polyamines stimulated the activity of purified ATP13A2, while neurodegenerative disease mutants were functionally impaired to a degree that correlated with the disease phenotype. Shaun, a senior post-doc in the team further demonstrated that ATP13A2 promotes cellular polyamine uptake via endocytosis and transports polyamines into the cytosol, which highlights a role for endo-lysosomes in cellular polyamine uptake. Defective lysosomal polyamine export leads to lysosomal dysfunction, rupture and lysosome-dependent cell death, which may be implicated in Parkinson's disease.
JANUARY 2020, Nature
Tine and Danny investigated the relationship between the five mammalian P5 isoforms ATP13A1-5 in a comparative study. Alongside phylogenetic analyses we shed light on the structural and functional aspects of the different isoforms in addition to investigating their subcellular localisation and yeast complimentarity.
MARCH 2018, PLOS ONE
Parkinson disease related ATP13A2 evolved early in animal evolution