Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1

By Jaime N. Guzmán, Javier Sánchez-Padilla, D. Wokosin, Jyothisri Kondapalli, E. Ilijic, P. Schumacker, J. Surmeier. Nature, 2010

833 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Geriatrics and Gerontology, Neurology

View Paper: https://www.semanticscholar.org/paper/18a8ccba7b791dcf28a7921b5076a2754078d1b9

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Citations in the corpus

Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling (2013, positive): “Using CD4 T cells isolated from transgenic mice expressing a mitochondrial-targeted redox-sensitive GFP (mitoroGFP) (Guzman et al., 2010), we found that mROS spiked 10 min after stimulation and were maintained at a higher level than baseline through 120min (Figure 2A).”
Synaptic energy use and supply. (2012, neutral): “Producing this ATP leads to oxidative stress (Guzman et al., 2010) that can uncouple or depolarize mitochondria.”
13 reasons why the brain is susceptible to oxidative stress (2018, background): “tochondrial O2/H2O2 axis controls their autonomous pace-making capacity [288].”
PINK1- and Parkin-mediated mitophagy at a glance (2012, background): “Although it is still not known why dopaminergic neurons appear to be more susceptible to mitochondrial damage than other tissues, one indication is that pacemaker activity causes waves of mitochondrial reactive oxygen species that might generate damage (Guzman et al., 2010).”
The energy cost of action potential propagation in dopamine neurons: clues to susceptibility in Parkinson's disease (2013, background): “…including mitochondrial dysfunction, protein mishandling, inflammation, oxidative stress, genetic and environmental factors, and normal ageing (Chan et al., 2007; Sulzer, 2007; Schapira, 2008; Gasser, 2010; Guzman et al., 2010; Martin et al., 2010; Obeso et al., 2010; Surmeier et al., 2010a,b).”
Unravelling the Biological Roles of Reactive Oxygen Species (2011, background): “Finally, using cell-specific promoters, these sensors can be introduced into the genome to generate transgenic animals that demonstrate cell- and region-specific expression of the sensor (Guzman et al., 2010).”
Role of mitochondrial ROS in the brain: from physiology to neurodegeneration (2018, background): “[56] Guzman JN, Sanchez-Padilla J, Wokosin D, Kondapalli J, Ilijic E, Schumacker PT, & Surmeier DJ (2010) Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1.”
Oxidative stress in the aging substantia nigra and the etiology of Parkinson's disease (2019, background): “The endogenous function of DJ‐1 may also protect against ROS generated by the calcium pacemaking activity of SNc dopamine neurons under physiological conditions (Guzman et al., 2010).”