ParkinsonFranceV1, Main, Exploration, bibRecord, 001103

Lysosomal dysfunction in Parkinson disease

Identifieur interne : 001103 ( Main/Exploration ); précédent : 001102; suivant : 001104

Lysosomal dysfunction in Parkinson disease

Auteurs : Benjamin Dehay [France] ; Marta Martinez-Vicente [Espagne] ; Alfredo Ramirez [Allemagne] ; Celine Perier [Espagne] ; Christine Klein [Allemagne] ; Miquel Vila [Espagne] ; Erwan Bezard [France]

Source :

Autophagy [ 1554-8627 ] ; 2012.

RBID : PMC:3442887

English descriptors

KwdEn :
- Autophagy, Dopaminergic Neurons (metabolism), Dopaminergic Neurons (pathology), Humans, Lewy Bodies (metabolism), Lysosomes (metabolism), Lysosomes (pathology), Parkinson Disease (genetics), Parkinson Disease (physiopathology), Proton-Translocating ATPases (deficiency), Proton-Translocating ATPases (genetics).
MESH :
- chemical , deficiency : Proton-Translocating ATPases.
- genetics : Parkinson Disease, Proton-Translocating ATPases.
- metabolism : Dopaminergic Neurons, Lewy Bodies, Lysosomes.
- pathology : Dopaminergic Neurons, Lysosomes.
- physiopathology : Parkinson Disease.
- Autophagy, Humans.

Abstract

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.

Url:

DOI: 10.4161/auto.21011
PubMed: 22885599
PubMed Central: 3442887

Affiliations:

Allemagne, Espagne, France

Le document en format XML

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<front><div type="abstract" xml:lang="en"><p>Mutations in <italic>ATP13A2</italic>
 (PARK9) cause an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia called Kufor-Rakeb Syndrome (KRS). The <italic>ATP13A2</italic>
 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.</p>
</div>
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La maladie de Parkinson en France (serveur d'exploration)

Lysosomal dysfunction in Parkinson disease

Lysosomal dysfunction in Parkinson disease

Source :

English descriptors

Abstract

Links toward previous steps (curation, corpus...)

Le document en format XML

Pour manipuler ce document sous Unix (Dilib)

Pour mettre un lien sur cette page dans le réseau Wicri

Pour générer des pages wiki

	La maladie de Parkinson en France (serveur d'exploration)
	Attention, ce site est en cours de développement ! Attention, site généré par des moyens informatiques à partir de corpus bruts. Les informations ne sont donc pas validées.