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.
Team
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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
ATP13A2 deficiency and dysfunction is associated with impaired mitochondrial health. Moreover, functional ATP13A2 has been reported to provide protection against mitochondrial neurotoxins such as the pesticide rotenone (an inhibitor of complex I in the mitochondrial electron transport chain). We wondered whether polyamines transported out of the lysosome by ATP13A2 can establish such mitochondrial protective effect. Indeed, during the first two years of her PhD project, Stephanie showed that polyamines transported by ATP13A2 can mitigate mitochondrial-generated oxidative stress. As a result, the initiation of a specific ATF4/CHOP marked stress response and cell death is prevented. Interestingly, the polyamines transported by ATP13A2 are redistributed to the mitochondria, where they may have a local anti-oxidant effect. Key results were recapitulated in a Caenorhabditis elegans model, emphasizing that this newly identified cell protective mechanism is highly conserved
DECEMBER 2020, PNAS
ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress