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Publication

Deficient lysosomal polyamine export is at the heart of ATP13A2-associated neurodegeneration

Book - Dissertation

ATP13A2/PARK9 encodes a ubiquitously expressed late endo-/lysosomal orphan transporter that is implicated in a spectrum of neurodegenerative disorders, including Kufor-Rakeb syndrome and Parkinson's disease. ATP13A2 plays a neuroprotective role, since its loss leads to compromised lysosomal function, impaired autophagy and mitochondrial fragmentation. Furthermore, ATP13A2 offers protection to α-synuclein, the major aggregated protein in brain plaques of PD patients, to heavy metal toxicity and to PD-inducing mitochondrial complex I inhibitors. However, the protective mechanism remains unclear. The N-terminus of ATP13A2 interacts with the signaling lipids PA and PI(3,5)P2 and in a first study, we demonstrated that PA and PI(3,5)P2 are required for ATP13A2-mediated protection against mitochondrial stress and heavy metal toxicity. Our findings suggest a general lipid-dependent ATP13A2 activation mechanism that relieves N-terminal auto-inhibition. In a second study, we established ATP13A2 as a lysosomal polyamine exporter with the highest affinity for SPM. The polyamines SPM and SPD stimulate the turnover of purified ATP13A2, while disease mutants are functionally impaired to a degree that correlates with the severity of the disease phenotype. We further demonstrated that ATP13A2 promotes cellular polyamine uptake via endocytosis and sequesters polyamines to the cytosol, which highlights a role for endo-lysosomes in cellular polyamine uptake. Polyamines increased toxicity in SH-SY5Y cells, neurons and nematodes with loss of ATP13A2 or its orthologues. At the cellular level, toxicity was manifested as lysosomal dysfunction, lysosomal rupture and cathepsin B activation. Thus, defective lysosomal polyamine export appears to be a new mechanism for lysosome-dependent cell death that may be implicated in neurodegeneration. With this study, we shed light on the mysterious mammalian PTS, which has been unknown for decades. Furthermore, we establish KRS as a novel polyamine-associated neurological disorder and our findings further suggest that a disturbed polyamine homeostasis is also implicated in other ATP13A2-associated diseases. Stimulating lysosomal polyamine export may therefore be a strategy for neuroprotective therapy. Targeting the N-terminal lipid binding sites of ATP13A2 might offer a therapeutic modality to activate ATP13A2 and stimulate lysosomal polyamine export.
Publication year:2020
Accessibility:Open