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

B. Dehay, A. Ramirez, M. Martinez-Vicente, C. Perier, M.-H. Canron, E. Doudnikoff, A. Vital, M. Vila, C. Klein, E. Bezard
Proceedings of the National Academy of Sciences. 2012-05-30; 109(24): 9611-9616
DOI: 10.1073/pnas.1112368109

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1. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9611-6. doi:
10.1073/pnas.1112368109. Epub 2012 May 30.

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

Dehay B(1), Ramirez A, Martinez-Vicente M, Perier C, Canron MH, Doudnikoff E,
Vital A, Vila M, Klein C, Bezard E.

Author information:
(1)Insitute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre
National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076
Bordeaux, France.

Comment in
Mov Disord. 2012 Aug;27(9):1092.

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 stable ATP13A2-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.

DOI: 10.1073/pnas.1112368109
PMCID: PMC3386132
PMID: 22647602 [Indexed for MEDLINE]


Auteurs Bordeaux Neurocampus