Paraquat neurotoxicity is mediated by a Bak-dependent mechanism.
Paraquat (PQ) causes selective degeneration of dopaminergic neurons in the substantia nigra pars compacta, reproducing an important pathological feature of Parkinson disease. Oxidative stress, c-Jun N-terminal kinase activation, and alpha-synuclein aggregation are each induced by PQ, but details of the cell death mechanisms involved remain unclear. We have identified a Bak-dependent cell death mechanism that is required for PQ-induced neurotoxicity. PQ induced morphological and biochemical features that were consistent with apoptosis, including dose-dependent cytochrome c release, with subsequent caspase-3 and poly(ADP-ribose) polymerase cleavage. Changes in nuclear morphology and loss of viability were blocked by cycloheximide, caspase inhibitor, and Bcl-2 overexpression. Evaluation of Bcl-2 family members showed that PQ induced high levels of Bak, Bid, BNip3, and Noxa. Small interfering RNA-mediated knockdown of BNip3, Noxa, and Bak each protected cells from PQ, but Bax knockdown did not. Finally, we tested the sensitivity of Bak-deficient mice and found them to be resistant to PQ treatments that depleted tyrosine hydroxylase immuno-positive neurons in the substantia nigra pars compacta of wild-type mice.
Division of Biomedical Sciences, University of California, Riverside, California 92521 and the.
Qingyan
Q
Fei
Parkinson's Institute, Sunnyvale, California 94085.
Alison L
AL
McCormack
Parkinson's Institute, Sunnyvale, California 94085.
Donato A
DA
Di Monte
Division of Biomedical Sciences, University of California, Riverside, California 92521 and the. Electronic address: doug.ethell@ucr.edu.
Douglas W
DW
Ethell
D000818:Animals; D017209:Apoptosis; D053148:Caspase 3 / Q000378:metabolism; D002470:Cell Survival; D003513:Cycloheximide / Q000494:pharmacology; D005786:Gene Expression Regulation; D006540:Herbicides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D010269:Paraquat / Q000494:pharmacology*; D010300:Parkinson Disease / Q000378:metabolism*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000378:metabolism*
C494772:BAK1 protein, human; D006540:Herbicides; D011500:Protein Synthesis Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D003513:Cycloheximide; D011065:Poly(ADP-ribose) Polymerases; D053148:Caspase 3; D010269:Paraquat