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), 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.
Pubmed ID: 15603737 RIS Download
Adaptor Proteins, Signal Transducing | Amino Acid Sequence | Animals | Carrier Proteins | Cell Line, Tumor | Dopamine | HSP70 Heat-Shock Proteins | Humans | Mice | Molecular Sequence Data | NIH 3T3 Cells | Nerve Degeneration | Parkinson Disease | Proto-Oncogene Proteins c-bcl-2 | Rats | Ubiquitin-Protein Ligases