title: Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson's disease.
abstract: Mitochondrial oxidant stress is widely viewed as being critical to pathogenesis in Parkinson's disease. But the origins of this stress are poorly defined. One possibility is that it arises from the metabolic demands associated with regenerative activity. To test this hypothesis, we characterized neurons in the dorsal motor nucleus of the vagus (DMV), a population of cholinergic neurons that show signs of pathology in the early stages of Parkinson's disease, in mouse brain slices. DMV neurons were slow, autonomous pacemakers with broad spikes, leading to calcium entry that was weakly buffered. Using a transgenic mouse expressing a redox-sensitive optical probe targeted to the mitochondrial matrix, we found that calcium entry during pacemaking created a basal mitochondrial oxidant stress. Knocking out DJ-1 (also known as PARK7), a gene associated with early-onset Parkinson's disease, exacerbated this stress. These results point to a common mechanism underlying mitochondrial oxidant stress in Parkinson's disease and a therapeutic strategy to ameliorate it.
authors.affiliation: Department of Physiology, Feinberg School of Medicine, Northwestern University Chicago, Illinois, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Goldberg
authors.forename: Jaime N
authors.initials: JN
authors.lastname: Guzman
authors.forename: Chad M
authors.initials: CM
authors.lastname: Estep
authors.forename: Ema
authors.initials: E
authors.lastname: Ilijic
authors.forename: Jyothisri
authors.initials: J
authors.lastname: Kondapalli
authors.forename: Javier
authors.initials: J
authors.lastname: Sanchez-Padilla
authors.forename: D James
authors.initials: DJ
authors.lastname: Surmeier
mesh_terms: D000818:Animals; D001683:Biological Clocks / Q000235:genetics / Q000502:physiology; D002118:Calcium / Q000009:adverse effects* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism*; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology*; D010300:Parkinson Disease / Q000209:etiology*; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D014630:Vagus Nerve / Q000378:metabolism* / Q000502:physiology
chemical_list: D015513:Oncogene Proteins; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D002118:Calcium