Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration

Benjamin Dehay, Alfredo Ramirez, Marta Martinez-Vicente, Celine Perier, Marie Hélène Canron, Evelyne Doudnikoff, Anne Vital, Miquel Vila, Christine Klein, Erwan Bezard

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191 Citations (Scopus)

Abstract

Parkinson disease (PD) is a progressive neurodegenerative disorder pathologically characterized by the loss of dopaminergic neurons from the substantia nigra pars compacta and the presence, in affected brain regions, of protein inclusions named Lewy bodies (LBs). The ATP13A2 gene (locus PARK9) encodes the protein ATP13A2, a lysosomal type 5 P-type ATPase that is linked to autosomal recessive familial parkinsonism. The physiological function of ATP13A2, and hence its role in PD, remains to be elucidated. Here, we show that PD-linked mutations in ATP13A2 lead to several lysosomal alterations in ATP13A2 PD patient-derived fibroblasts, including impaired lysosomal acidification, decreased proteolytic processing of lysosomal enzymes, reduced degradation of lysosomal substrates, and diminished lysosomal-mediated clearance of autophagosomes. Similar alterations are observed in stableATP13A2- knockdown dopaminergic cell lines,which are associated with cell death. Restoration of ATP13A2 levels in ATP13A2-mutant/ depleted cells restores lysosomal function and attenuates cell death. Relevant to PD, ATP13A2 levels are decreased in dopaminergic nigral neurons from patients with PD, in which ATP13A2 mostly accumulates within Lewy bodies. Our results unravel an instrumental role of ATP13A2 deficiency on lysosomal function and cell viability and demonstrate the feasibility and therapeutic potential of modulating ATP13A2 levels in the context of PD.
Original languageEnglish
Pages (from-to)9611-9616
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number24
DOIs
Publication statusPublished - 12 Jun 2012

Keywords

  • Autophagy
  • Lysosome
  • Neurodegeneration

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    Dehay, B., Ramirez, A., Martinez-Vicente, M., Perier, C., Canron, M. H., Doudnikoff, E., Vital, A., Vila, M., Klein, C., & Bezard, E. (2012). Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration. Proceedings of the National Academy of Sciences of the United States of America, 109(24), 9611-9616. https://doi.org/10.1073/pnas.1112368109