Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1.
Parkinson's disease is a pervasive, ageing-related neurodegenerative disease the cardinal motor symptoms of which reflect the loss of a small group of neurons, the dopaminergic neurons in the substantia nigra pars compacta (SNc). Mitochondrial oxidant stress is widely viewed as being responsible for this loss, but why these particular neurons should be stressed is a mystery. Here we show, using transgenic mice that expressed a redox-sensitive variant of green fluorescent protein targeted to the mitochondrial matrix, that the engagement of plasma membrane L-type calcium channels during normal autonomous pacemaking created an oxidant stress that was specific to vulnerable SNc dopaminergic neurons. The oxidant stress engaged defences that induced transient, mild mitochondrial depolarization or uncoupling. The mild uncoupling was not affected by deletion of cyclophilin D, which is a component of the permeability transition pore, but was attenuated by genipin and purine nucleotides, which are antagonists of cloned uncoupling proteins. Knocking out DJ-1 (also known as PARK7 in humans and Park7 in mice), which is a gene associated with an early-onset form of Parkinson's disease, downregulated the expression of two uncoupling proteins (UCP4 (SLC25A27) and UCP5 (SLC25A14)), compromised calcium-induced uncoupling and increased oxidation of matrix proteins specifically in SNc dopaminergic neurons. Because drugs approved for human use can antagonize calcium entry through L-type channels, these results point to a novel neuroprotective strategy for both idiopathic and familial forms of Parkinson's disease.
Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Jaime N
JN
Guzman
Javier
J
Sanchez-Padilla
David
D
Wokosin
Jyothisri
J
Kondapalli
Ema
E
Ilijic
Paul T
PT
Schumacker
D James
DJ
Surmeier
D000818:Animals; D001683:Biological Clocks / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000378:metabolism / Q000494:pharmacology; D020013:Calcium Signaling; D000081406:Peptidyl-Prolyl Isomerase F; D021983:Cyclophilins / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D017353:Gene Deletion; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D057889:Iridoid Glycosides / Q000494:pharmacology; D039823:Iridoids; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D015513:Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D011687:Purines / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D000071256:Uncoupling Protein 1
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D000081406:Peptidyl-Prolyl Isomerase F; D004095:Dihydropyridines; D007473:Ion Channels; D057889:Iridoid Glycosides; D039823:Iridoids; D024101:Mitochondrial Proteins; D015513:Oncogene Proteins; C000631446:PPIF protein, mouse; D011687:Purines; D000071256:Uncoupling Protein 1; D013481:Superoxides; C038806:1,4-dihydropyridine; C007834:genipin; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D021983:Cyclophilins; D002118:Calcium; D004298:Dopamine