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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

Authors

  • Kalia SK
  • Lee S
  • Smith PD
  • Liu L
  • Crocker SJ
  • Thorarinsdottir TE
  • Glover JR
  • Fon EA
  • Park DS
  • Lozano AM

Journal

Neuron

Publication Data

December 16, 2004

Associated Grants

None

Mesh Terms

  • 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