P5 ATPases - Pioneering the Discovery of Mammalian Polyamine Transporters
Phylogenetic analyses of early genomic data uncovered a fifth P-type ATPase subfamily, P5-type ATPases, found exclusively in eukaryotes. For years, their substrate specificity and precise cellular roles remained enigmatic. Today, several of the five human P5 ATPases have gained significant attention due to their implication in diverse human disorders.
Our lab pioneered the discovery of ATP13A2, a P5B-ATPase, as the first mammalian polyamine transporter. ATP13A2 is genetically linked to a spectrum of neurodegenerative diseases, including Kufor-Rakeb syndrome, early-onset Parkinson’s disease (PD), neuronal ceroid lipofuscinosis (NCL), and amyotrophic lateral sclerosis (ALS). Importantly, our work revealed that defective lysosomal polyamine export constitutes a novel pathogenic pathway driving (lysosome-dependent cell death in) neurodegeneration.
Building on these findings, LabCTS is pursuing multiple lines of research related to ATP13A2, next to fundamental research studies, also including a polyamine biomarker study in Parkinson’s disease and a patient cohort study, both funded by the MJFF.
We are also investigating other P5B-ATPase isoforms, such as ATP13A3 in pulmonary arterial hypertension and ATP13A4 in neurodevelopmental 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.
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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
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DECEMBER 2020, PNAS
ATP13A2-mediated endo-lysosomal polyamine export counters mitochondrial oxidative stress