Lysosomal dysfunction in Parkinson disease: ATP13A2 gets into the groove.

Benjamin Dehay, Marta Martinez-Vicente, Alfredo Ramirez, Celine Perier, Christine Klein, Miquel Vila, Erwan Bezard
Autophagy. 2012-09-14; 8(9): 1389-1391
DOI: 10.4161/auto.21011

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1. Autophagy. 2012 Sep;8(9):1389-91. doi: 10.4161/auto.21011. Epub 2012 Aug 13.

Lysosomal dysfunction in Parkinson disease: ATP13A2 gets into the groove.

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

Author information:
(1)Institut des Maladies Neurodégénératives, Université de Bordeaux, CNRS UMR
5293, Bordeaux, France.

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.

DOI: 10.4161/auto.21011
PMCID: PMC3442887
PMID: 22885599 [Indexed for MEDLINE]

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