Document Detail

Lysosomal dysfunction in Parkinson disease: ATP13A2 gets into the groove.
MedLine Citation:
PMID:  22885599     Owner:  NLM     Status:  MEDLINE    
Mutations in ATP13A2 (PARK9) cause an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia called Kufor-Rakeb Syndrome (KRS). The ATP13A2 gene encodes a transmembrane lysosomal P5-type ATPase (ATP13A2) whose physiological function in mammalian cells, and hence its potential role in Parkinson disease (PD), remains elusive. In this context, we have recently shown that KRS-linked mutations in ATP13A2 leads to several lysosomal alterations in ATP13A2 KRS 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 (AP). 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 is able to restore lysosomal function and attenuate cell death. Relevant to PD, we have determined that ATP13A2 levels are decreased in dopaminergic nigral neurons from sporadic PD patients. Interestingly in these patients, the main signal of ATP13A2 is detected in the Lewy bodies. Our results unravel an instrumental role of ATP13A2 in lysosomal function and in cell viability. Altogether, our results validate ATP13A2 as a likely therapeutic target against PD degeneration.
Benjamin Dehay; Marta Martinez-Vicente; Alfredo Ramirez; Celine Perier; Christine Klein; Miquel Vila; Erwan Bezard
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Publication Detail:
Type:  Journal Article     Date:  2012-08-13
Journal Detail:
Title:  Autophagy     Volume:  8     ISSN:  1554-8635     ISO Abbreviation:  Autophagy     Publication Date:  2012 Sep 
Date Detail:
Created Date:  2012-09-07     Completed Date:  2013-01-16     Revised Date:  2013-09-02    
Medline Journal Info:
Nlm Unique ID:  101265188     Medline TA:  Autophagy     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1389-91     Citation Subset:  IM    
Institut des Maladies Neurodégénératives, Université de Bordeaux, CNRS UMR 5293, Bordeaux, France.
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MeSH Terms
Dopaminergic Neurons / metabolism,  pathology
Lewy Bodies / metabolism
Lysosomes / metabolism,  pathology*
Parkinson Disease / genetics*,  physiopathology*
Proton-Translocating ATPases / deficiency,  genetics*
Reg. No./Substance:
EC protein, human; EC ATPases

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