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.
Kalia
Suneil K
SK
Applied and Interventional Research, Toronto Western Hospital Research Institute, University Health Network, University of Toronto, 399 Bathurst Street, Toronto, Ontario M5T 2S8, Canada.
Lee
Sang
S
Smith
Patrice D
PD
Liu
Li
L
Crocker
Stephen J
SJ
Thorarinsdottir
Thorhildur E
TE
Glover
John R
JR
Fon
Edward A
EA
Park
David S
DS
Lozano
Andres M
AM
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000502:physiology*; D000595:Amino Acid Sequence; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D004298:Dopamine / Q000235:genetics / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; C496515:BAG5 protein, human; C496516:BAG5 protein, mouse; C496514:Bag5 protein, rat; D002352:Carrier Proteins; D018840:HSP70 Heat-Shock Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D004298:Dopamine