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.

Department of Neuroscience

Kalia, S.K. (Suneil K.), Lee, S. (Sang), Smith, P, Liu, L. (Li), Crocker, S.J. (Stephen J.), Thorarinsdottir, T.E. (Thorhildur E.), … Lozano, A.M. (Andres M.). (2004). BAG5 inhibits parkin and enhances dopaminergic neuron degeneration. Neuron, 44(6), 931–945. doi:10.1016/j.neuron.2004.11.026