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.

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Persistent URL dx.doi.org/10.1016/j.neuron.2004.11.026
Journal Neuron
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