Journal Article

Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson's disease

Kondapalli, Jyothisri, Goldberg, Joshua A, Estep, Chad M, Sanchez-Padilla, Javier, Surmeier, D James, Ilijic, Ema, Guzman, Jaime N

2012

Overview

The pathology in Parkinson's disease is known to extend beyond mesencephalic dopaminergic neurons, but it is unclear why. Here the authors show that vulnerable neurons in the dorsal motor nucleus of the vagus have similar physiological features, including basal mitochondrial oxidant stress, providing an insight into the distributed disease pathology. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/378/1689/1718 / 631/378/340 / Animal Genetics and Genomics / Animals / Behavioral Sciences / Biological Clocks - genetics / Biological Clocks - physiology / Biological Techniques / Biomedical and Life Sciences / Biomedicine / Calcium - adverse effects / Calcium - metabolism / Calcium, Dietary / Metabolism / Mice / Mice, Knockout / Mice, Transgenic / Mitochondria - metabolism / Mutation / Neurobiology / Neurons / Neurosciences / Oncogene Proteins - genetics / Oncogene Proteins - metabolism / Oxidative stress / Oxidative Stress - genetics / Oxidative Stress - physiology / Pacemakers / Parkinson Disease - etiology / Parkinson's disease / Pathogenesis / Pathology / Peroxiredoxins / Physiological aspects / Protein Deglycase DJ-1 / Risk factors / Vagus Nerve - metabolism / Vagus Nerve - physiology