BAG5 Inhibits Parkin and Enhances Dopaminergic Neuron Degeneration

• DOI: 10.1016/j.neuron.2004.11.026
• Publication Date: 2004-12-16T20:34:26Z
• Authors: Suneil K. Kalia; Sang Lee; Patrice D. Smith; Li Liu; Stephen J. Crocker; Thorhildur E. Tho...; John R. Glover; Edward A. Fon; David S. Park; Andres M. Lozano
• Keywords: 0303 health sciences; Neuroscience(all); Dopamine; Ubiquitin-Protein Ligases; Molecular Sequence Data; Parkinson Disease; Rats; Mice; 03 medical and health sciences; Proto-Oncogene Proteins c-bcl-2; Cell Line, Tumor; Nerve Degeneration; NIH 3T3 Cells; Animals; Humans; HSP70 Heat-Shock Proteins; Amino Acid Sequence; Carrier Proteins; Adaptor Proteins, Signal Transducing

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.