Journal
NEUROBIOLOGY OF DISEASE
Volume 139, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2020.104786
Keywords
ATP13A2; Catp-6; Lysosomes; Iron metabolism; Mitochondrial function; Urolithin A; Iron chelation; TFEB; Parkinson's disease; C. elegans
Categories
Funding
- NIH R21 grant [NS0957]
- Larry L. Hillblom Foundation
- NIH Office of Research Infrastructure Programs [P40 OD010440]
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Mutations in the human ATP13A2 gene are associated with an early-onset form of Parkinson's disease (PD) known as Kufor Rakeb Syndrome (KRS). Patients with KRS show increased iron deposition in the basal ganglia, suggesting iron toxicity-induced neurodegeneration as a potential pathogenesis associated with the ATP13A2 mutation. Previously we demonstrated that functional losses of ATP13A2 disrupt the lysosomes ability to store excess iron, leading to reduce survival of dopaminergic neuronal cells. To understand the possible mechanisms involved, we studied a Caenorhabditis elegans mutant defective in catp-6 function, an ortholog of human ATP13A2 gene. Here we show that catp-6 mutant worms have defective autophagy and lysosomal function, demonstrate characteristic PD phenotypes including reduced motor function and dysregulated iron metabolism. Additionally, these mutants have defective mitochondrial health, which is rescuable via iron chelation or mitophagy induction.
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