BAG5 inhibits parkin and enhances dopaminergic neuron degeneration

Suneil K Kalia; 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

doi:10.1016/j.neuron.2004.11.026

BAG5 inhibits parkin and enhances dopaminergic neuron degeneration

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

Authors

Suneil K Kalia¹, 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

Affiliation

¹ Applied and Interventional Research, Toronto Western Hospital Research Institute, University Health Network, University of Toronto, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.

PMID: 15603737
DOI: 10.1016/j.neuron.2004.11.026

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / physiology*
Amino Acid Sequence
Animals
Carrier Proteins / genetics
Carrier Proteins / physiology*
Cell Line, Tumor
Dopamine / genetics
Dopamine / metabolism*
HSP70 Heat-Shock Proteins / antagonists & inhibitors
HSP70 Heat-Shock Proteins / genetics
HSP70 Heat-Shock Proteins / metabolism
Humans
Mice
Molecular Sequence Data
NIH 3T3 Cells
Nerve Degeneration / genetics
Nerve Degeneration / metabolism
Nerve Degeneration / pathology*
Parkinson Disease / metabolism*
Parkinson Disease / pathology
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism*
Rats
Ubiquitin-Protein Ligases / antagonists & inhibitors*
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / metabolism*

Substances

Adaptor Proteins, Signal Transducing
BAG5 protein, human
BAG5 protein, mouse
Bag5 protein, rat
Carrier Proteins
HSP70 Heat-Shock Proteins
Proto-Oncogene Proteins c-bcl-2
Ubiquitin-Protein Ligases
parkin protein
Dopamine

Associated data

GENBANK/AY366364