ParkinsonCanadaV1, Main, Exploration, bibRecord, 000D07

Parkin-Dependent Degradation of the F-Box Protein Fbw7β Promotes Neuronal Survival in Response to Oxidative Stress by Stabilizing Mcl-1

Identifieur interne : 000D07 ( Main/Exploration ); précédent : 000D06; suivant : 000D08

Parkin-Dependent Degradation of the F-Box Protein Fbw7β Promotes Neuronal Survival in Response to Oxidative Stress by Stabilizing Mcl-1

Auteurs : Susanna Ekholm-Reed ; Matthew S. Goldberg ; Michael G. Schlossmacher ; Steven I. Reed

Source :

Molecular and Cellular Biology [ 0270-7306 ] ; 2013.

RBID : PMC:3753862

English descriptors

KwdEn :
- Amino Acid Sequence, Animals, Apoptosis, Cell Survival, Cells, Cultured, Disease Models, Animal, F-Box Proteins (chemistry), F-Box Proteins (genetics), F-Box Proteins (metabolism), Glycogen Synthase Kinase 3 (metabolism), HEK293 Cells, Humans, MAP Kinase Signaling System, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Multiprotein Complexes (metabolism), Mutation, Myeloid Cell Leukemia Sequence 1 Protein (metabolism), Neurons (cytology), Neurons (metabolism), Oxidative Stress, Parkinson Disease (genetics), Parkinson Disease (metabolism), Parkinson Disease (pathology), Protein Stability, Proteolysis, TOR Serine-Threonine Kinases (metabolism), Ubiquitin-Protein Ligases (chemistry), Ubiquitin-Protein Ligases (deficiency), Ubiquitin-Protein Ligases (genetics), Ubiquitin-Protein Ligases (metabolism).
MESH :
- chemical , chemistry : F-Box Proteins, Ubiquitin-Protein Ligases.
- chemical , deficiency : Ubiquitin-Protein Ligases.
- chemical , genetics : F-Box Proteins, Ubiquitin-Protein Ligases.
- chemical , metabolism : F-Box Proteins, Glycogen Synthase Kinase 3, Multiprotein Complexes, Myeloid Cell Leukemia Sequence 1 Protein, TOR Serine-Threonine Kinases, Ubiquitin-Protein Ligases.
- cytology : Neurons.
- genetics : Parkinson Disease.
- metabolism : Neurons, Parkinson Disease.
- pathology : Parkinson Disease.
- Amino Acid Sequence, Animals, Apoptosis, Cell Survival, Cells, Cultured, Disease Models, Animal, HEK293 Cells, Humans, MAP Kinase Signaling System, Mice, Mice, Inbred C57BL, Mice, Knockout, Molecular Sequence Data, Mutation, Oxidative Stress, Protein Stability, Proteolysis.

Abstract

Parkinson's disease (PD) is characterized by progressive loss of midbrain dopaminergic neurons resulting in motor dysfunction. While most PD is sporadic in nature, a significant subset can be linked to either dominant or recessive germ line mutations. PARK2, encoding the ubiquitin ligase parkin, is the most frequently mutated gene in hereditary Parkinson's disease. Here, we present evidence for a neuronal ubiquitin ligase cascade involving parkin and the multisubunit ubiquitin ligase SCF^Fbw7β. Specifically, parkin targets the SCF substrate adapter Fbw7β for proteasomal degradation. Furthermore, we show that the physiological role of parkin-mediated regulation of Fbw7β levels is the stabilization of the mitochondrial prosurvival factor Mcl-1, an SCF^Fbw7β target in neurons. We show that neurons depleted of parkin become acutely sensitive to oxidative stress due to an inability to maintain adequate levels of Mcl-1. Therefore, loss of parkin function through biallelic mutation of PARK2 may lead to death of dopaminergic neurons through unregulated SCF^Fbw7β-mediated ubiquitylation-dependent proteolysis of Mcl-1.

Url:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753862

DOI: 10.1128/MCB.00535-13
PubMed: 23858059
PubMed Central: 3753862

Affiliations:

Le document en format XML

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<term>Cell Survival</term>
<term>Cells, Cultured</term>
<term>Disease Models, Animal</term>
<term>F-Box Proteins (chemistry)</term>
<term>F-Box Proteins (genetics)</term>
<term>F-Box Proteins (metabolism)</term>
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<term>Parkinson Disease (metabolism)</term>
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<term>Ubiquitin-Protein Ligases (metabolism)</term>
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<term>Ubiquitin-Protein Ligases</term>
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<term>Myeloid Cell Leukemia Sequence 1 Protein</term>
<term>TOR Serine-Threonine Kinases</term>
<term>Ubiquitin-Protein Ligases</term>
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<front><div type="abstract" xml:lang="en"><p>Parkinson's disease (PD) is characterized by progressive loss of midbrain dopaminergic neurons resulting in motor dysfunction. While most PD is sporadic in nature, a significant subset can be linked to either dominant or recessive germ line mutations. <italic>PARK2</italic>
, encoding the ubiquitin ligase parkin, is the most frequently mutated gene in hereditary Parkinson's disease. Here, we present evidence for a neuronal ubiquitin ligase cascade involving parkin and the multisubunit ubiquitin ligase SCF<sup>Fbw7β</sup>
. Specifically, parkin targets the SCF substrate adapter Fbw7β for proteasomal degradation. Furthermore, we show that the physiological role of parkin-mediated regulation of Fbw7β levels is the stabilization of the mitochondrial prosurvival factor Mcl-1, an SCF<sup>Fbw7β</sup>
 target in neurons. We show that neurons depleted of parkin become acutely sensitive to oxidative stress due to an inability to maintain adequate levels of Mcl-1. Therefore, loss of parkin function through biallelic mutation of <italic>PARK2</italic>
 may lead to death of dopaminergic neurons through unregulated SCF<sup>Fbw7β</sup>
-mediated ubiquitylation-dependent proteolysis of Mcl-1.</p>
</div>
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<name sortKey="Goldberg, Matthew S" sort="Goldberg, Matthew S" uniqKey="Goldberg M" first="Matthew S." last="Goldberg">Matthew S. Goldberg</name>
<name sortKey="Reed, Steven I" sort="Reed, Steven I" uniqKey="Reed S" first="Steven I." last="Reed">Steven I. Reed</name>
<name sortKey="Schlossmacher, Michael G" sort="Schlossmacher, Michael G" uniqKey="Schlossmacher M" first="Michael G." last="Schlossmacher">Michael G. Schlossmacher</name>
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La maladie de Parkinson au Canada (serveur d'exploration)

Parkin-Dependent Degradation of the F-Box Protein Fbw7β Promotes Neuronal Survival in Response to Oxidative Stress by Stabilizing Mcl-1

Parkin-Dependent Degradation of the F-Box Protein Fbw7β Promotes Neuronal Survival in Response to Oxidative Stress by Stabilizing Mcl-1

Source :

English descriptors

Abstract

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

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Pour générer des pages wiki

	La maladie de Parkinson au Canada (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.