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. 2004 Dec 16;44(6):931-45.
doi: 10.1016/j.neuron.2004.11.026.

BAG5 inhibits parkin and enhances dopaminergic neuron degeneration

Suneil K Kalia  1 , Sang Lee, Patrice D Smith, Li Liu, Stephen J Crocker, Thorhildur E Thorarinsdottir, John R Glover, Edward A Fon, David S Park, Andres M Lozano
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Free article

BAG5 inhibits parkin and enhances dopaminergic neuron degeneration

Suneil K Kalia et al. Neuron. .
Free article

Abstract

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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Comment in

  • Parkin and Hsp70 sacked by BAG5.
    Chung KK, Dawson TM. Chung KK, et al. Neuron. 2004 Dec 16;44(6):899-901. doi: 10.1016/j.neuron.2004.12.007. Neuron. 2004. PMID: 15603730 Review.

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