BAG5 inhibits parkin and enhances dopaminergic neuron degeneration.
Identifieur interne : 002B96 ( Main/Exploration ); précédent : 002B95; suivant : 002B97BAG5 inhibits parkin and enhances dopaminergic neuron degeneration.
Auteurs : Suneil K. Kalia [Canada] ; Sang Lee ; Patrice D. Smith ; Li Liu ; Stephen J. Crocker ; Thorhildur E. Thorarinsdottir ; John R. Glover ; Edward A. Fon ; David S. Park ; Andres M. LozanoSource :
- Neuron [ 0896-6273 ] ; 2004.
English descriptors
- KwdEn :
- Adaptor Proteins, Signal Transducing (genetics), Adaptor Proteins, Signal Transducing (physiology), Amino Acid Sequence, Animals, Carrier Proteins (genetics), Carrier Proteins (physiology), Cell Line, Tumor, Dopamine (genetics), Dopamine (metabolism), HSP70 Heat-Shock Proteins (antagonists & inhibitors), HSP70 Heat-Shock Proteins (genetics), HSP70 Heat-Shock Proteins (metabolism), Humans, Mice, Molecular Sequence Data, NIH 3T3 Cells, Nerve Degeneration (genetics), Nerve Degeneration (metabolism), Nerve Degeneration (pathology), Parkinson Disease (metabolism), Parkinson Disease (pathology), Proto-Oncogene Proteins c-bcl-2 (genetics), Proto-Oncogene Proteins c-bcl-2 (metabolism), Rats, Ubiquitin-Protein Ligases (antagonists & inhibitors), Ubiquitin-Protein Ligases (genetics), Ubiquitin-Protein Ligases (metabolism).
- MESH :
- chemical , antagonists & inhibitors : HSP70 Heat-Shock Proteins, Ubiquitin-Protein Ligases.
- chemical , genetics : Adaptor Proteins, Signal Transducing, Carrier Proteins, Dopamine, HSP70 Heat-Shock Proteins, Proto-Oncogene Proteins c-bcl-2, Ubiquitin-Protein Ligases.
- chemical , metabolism : Dopamine, HSP70 Heat-Shock Proteins, Proto-Oncogene Proteins c-bcl-2, Ubiquitin-Protein Ligases.
- chemical , physiology : Adaptor Proteins, Signal Transducing, Carrier Proteins.
- genetics : Nerve Degeneration.
- metabolism : Nerve Degeneration, Parkinson Disease.
- pathology : Nerve Degeneration, Parkinson Disease.
- Amino Acid Sequence, Animals, Cell Line, Tumor, Humans, Mice, Molecular Sequence Data, NIH 3T3 Cells, Rats.
Abstract
Loss-of-function mutations in the parkin gene, which encodes an E3 ubiquitin ligase, are the major cause of early-onset Parkinson's disease (PD). Decreases in parkin activity may also contribute to neurodegeneration in sporadic forms of PD. Here, we show that bcl-2-associated athanogene 5 (BAG5), a BAG family member, directly interacts with parkin and the chaperone Hsp70. Within this complex, BAG5 inhibits both parkin E3 ubiquitin ligase activity and Hsp70-mediated refolding of misfolded proteins. BAG5 enhances parkin sequestration within protein aggregates and mitigates parkin-dependent preservation of proteasome function. Finally, BAG5 enhances dopamine neuron death in an in vivo model of PD, whereas a mutant that inhibits BAG5 activity attenuates dopaminergic neurodegeneration. This contrasts with the antideath functions ascribed to BAG family members and suggests a potential role for BAG5 in promoting neurodegeneration in sporadic PD through its functional interactions with parkin and Hsp70.
DOI: 10.1016/j.neuron.2004.11.026
PubMed: 15603737
Affiliations:
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Kalia</name><affiliation wicri:level="1"><nlm:affiliation>Applied and Interventional Research, Toronto Western Hospital Research Institute, University Health Network, University of Toronto, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Applied and Interventional Research, Toronto Western Hospital Research Institute, University Health Network, University of Toronto, 399 Bathurst Street, Toronto, Ontario M5T 2S8</wicri:regionArea><wicri:noRegion>Ontario M5T 2S8</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Sang" sort="Lee, Sang" uniqKey="Lee S" first="Sang" last="Lee">Sang Lee</name></author><author><name sortKey="Smith, Patrice D" sort="Smith, Patrice D" uniqKey="Smith P" first="Patrice D" last="Smith">Patrice D. Smith</name></author><author><name sortKey="Liu, Li" sort="Liu, Li" uniqKey="Liu L" first="Li" last="Liu">Li Liu</name></author><author><name sortKey="Crocker, Stephen J" sort="Crocker, Stephen J" uniqKey="Crocker S" first="Stephen J" last="Crocker">Stephen J. Crocker</name></author><author><name sortKey="Thorarinsdottir, Thorhildur E" sort="Thorarinsdottir, Thorhildur E" uniqKey="Thorarinsdottir T" first="Thorhildur E" last="Thorarinsdottir">Thorhildur E. Thorarinsdottir</name></author><author><name sortKey="Glover, John R" sort="Glover, John R" uniqKey="Glover J" first="John R" last="Glover">John R. Glover</name></author><author><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name></author><author><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S" last="Park">David S. 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Kalia</name><affiliation wicri:level="1"><nlm:affiliation>Applied and Interventional Research, Toronto Western Hospital Research Institute, University Health Network, University of Toronto, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.</nlm:affiliation><country xml:lang="fr">Canada</country><wicri:regionArea>Applied and Interventional Research, Toronto Western Hospital Research Institute, University Health Network, University of Toronto, 399 Bathurst Street, Toronto, Ontario M5T 2S8</wicri:regionArea><wicri:noRegion>Ontario M5T 2S8</wicri:noRegion></affiliation></author><author><name sortKey="Lee, Sang" sort="Lee, Sang" uniqKey="Lee S" first="Sang" last="Lee">Sang Lee</name></author><author><name sortKey="Smith, Patrice D" sort="Smith, Patrice D" uniqKey="Smith P" first="Patrice D" last="Smith">Patrice D. Smith</name></author><author><name sortKey="Liu, Li" sort="Liu, Li" uniqKey="Liu L" first="Li" last="Liu">Li Liu</name></author><author><name sortKey="Crocker, Stephen J" sort="Crocker, Stephen J" uniqKey="Crocker S" first="Stephen J" last="Crocker">Stephen J. Crocker</name></author><author><name sortKey="Thorarinsdottir, Thorhildur E" sort="Thorarinsdottir, Thorhildur E" uniqKey="Thorarinsdottir T" first="Thorhildur E" last="Thorarinsdottir">Thorhildur E. Thorarinsdottir</name></author><author><name sortKey="Glover, John R" sort="Glover, John R" uniqKey="Glover J" first="John R" last="Glover">John R. Glover</name></author><author><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name></author><author><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S" last="Park">David S. Park</name></author><author><name sortKey="Lozano, Andres M" sort="Lozano, Andres M" uniqKey="Lozano A" first="Andres M" last="Lozano">Andres M. 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Decreases in parkin activity may also contribute to neurodegeneration in sporadic forms of PD. Here, we show that bcl-2-associated athanogene 5 (BAG5), a BAG family member, directly interacts with parkin and the chaperone Hsp70. Within this complex, BAG5 inhibits both parkin E3 ubiquitin ligase activity and Hsp70-mediated refolding of misfolded proteins. BAG5 enhances parkin sequestration within protein aggregates and mitigates parkin-dependent preservation of proteasome function. Finally, BAG5 enhances dopamine neuron death in an in vivo model of PD, whereas a mutant that inhibits BAG5 activity attenuates dopaminergic neurodegeneration. This contrasts with the antideath functions ascribed to BAG family members and suggests a potential role for BAG5 in promoting neurodegeneration in sporadic PD through its functional interactions with parkin and Hsp70.</div></front></TEI><affiliations><list><country><li>Canada</li></country></list><tree><noCountry><name sortKey="Crocker, Stephen J" sort="Crocker, Stephen J" uniqKey="Crocker S" first="Stephen J" last="Crocker">Stephen J. Crocker</name><name sortKey="Fon, Edward A" sort="Fon, Edward A" uniqKey="Fon E" first="Edward A" last="Fon">Edward A. Fon</name><name sortKey="Glover, John R" sort="Glover, John R" uniqKey="Glover J" first="John R" last="Glover">John R. Glover</name><name sortKey="Lee, Sang" sort="Lee, Sang" uniqKey="Lee S" first="Sang" last="Lee">Sang Lee</name><name sortKey="Liu, Li" sort="Liu, Li" uniqKey="Liu L" first="Li" last="Liu">Li Liu</name><name sortKey="Lozano, Andres M" sort="Lozano, Andres M" uniqKey="Lozano A" first="Andres M" last="Lozano">Andres M. Lozano</name><name sortKey="Park, David S" sort="Park, David S" uniqKey="Park D" first="David S" last="Park">David S. Park</name><name sortKey="Smith, Patrice D" sort="Smith, Patrice D" uniqKey="Smith P" first="Patrice D" last="Smith">Patrice D. Smith</name><name sortKey="Thorarinsdottir, Thorhildur E" sort="Thorarinsdottir, Thorhildur E" uniqKey="Thorarinsdottir T" first="Thorhildur E" last="Thorarinsdottir">Thorhildur E. Thorarinsdottir</name></noCountry><country name="Canada"><noRegion><name sortKey="Kalia, Suneil K" sort="Kalia, Suneil K" uniqKey="Kalia S" first="Suneil K" last="Kalia">Suneil K. Kalia</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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