Document Detail


Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration.
MedLine Citation:
PMID:  22647602     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Benjamin Dehay; Alfredo Ramirez; Marta Martinez-Vicente; Celine Perier; Marie-Hélène Canron; Evelyne Doudnikoff; Anne Vital; Miquel Vila; Christine Klein; Erwan Bezard
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-05-30
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  109     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-06-13     Completed Date:  2012-08-28     Revised Date:  2013-06-24    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  9611-6     Citation Subset:  IM    
Affiliation:
Insitute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5293, 33076 Bordeaux, France. benjamin.dehay@u-bordeaux2.fr
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphatases / metabolism*
Cell Line
Gene Knockdown Techniques
Humans
Lysosomes / metabolism*
Parkinson Disease / enzymology,  metabolism,  pathology*
Chemical
Reg. No./Substance:
EC 3.6.1.-/Adenosine Triphosphatases
Comments/Corrections
Comment In:
Mov Disord. 2012 Aug;27(9):1092   [PMID:  23035259 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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