BAG5 Inhibits Parkin and Enhances Dopaminergic Neuron Degeneration

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...

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Bibliographic Details
Published in:Neuron (Cambridge, Mass.) Mass.), 2004-12, Vol.44 (6), p.931-945
Main Authors: Kalia, Suneil K., Lee, Sang, Smith, Patrice D., Liu, Li, Crocker, Stephen J., Thorarinsdottir, Thorhildur E., Glover, John R., Fon, Edward A., Park, David S., Lozano, Andres M.
Format: Article
Language:English
Subjects:
Adaptor Proteins, Signal Transducing - genetics
Adaptor Proteins, Signal Transducing - physiology
Adenoviruses
Amino Acid Sequence
Animals
Apoptosis
Carrier Proteins - genetics
Carrier Proteins - physiology
Cell division
Cell Line, Tumor
Dopamine - genetics
Dopamine - metabolism
HSP70 Heat-Shock Proteins - antagonists & inhibitors
HSP70 Heat-Shock Proteins - genetics
HSP70 Heat-Shock Proteins - metabolism
Humans
Mammals
Medical research
Mice
Microscopy
Molecular Sequence Data
Nerve Degeneration - genetics
Nerve Degeneration - metabolism
Nerve Degeneration - pathology
Neurodegeneration
Neurons
NIH 3T3 Cells
Parkinson Disease - metabolism
Parkinson Disease - pathology
Proteins
Proto-Oncogene Proteins c-bcl-2 - genetics
Proto-Oncogene Proteins c-bcl-2 - metabolism
Rats
Rodents
Ubiquitin-Protein Ligases - antagonists & inhibitors
Ubiquitin-Protein Ligases - genetics
Ubiquitin-Protein Ligases - metabolism
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Summary: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.
ISSN:0896-6273
1097-4199
DOI:10.1016/j.neuron.2004.11.026