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

Abstract

Parkinson's disease (PD) is a pervasive, aging-related neurodegenerative disease whose cardinal motor symptoms reflect the loss of a small group of neurons – dopaminergic neurons in the substantia nigra pars compacta (SNc)1. Mitochondrial oxidant stress is widely viewed as responsible for this loss2, but why these particular neurons should be stressed is a mystery. Using transgenic mice that expressed a redox-sensitive variant of green fluorescent protein targeted to the mitochondrial matrix, it was discovered that the unusual engagement of plasma membrane L-type calcium channels during normal autonomous pacemaking created an oxidant stress that was specific to vulnerable SNc dopaminergic neurons. This stress engaged defenses that induced transient, mild mitochondrial depolarization or uncoupling. The mild uncoupling was not affected by deletion of cyclophilin D, a component of the permeability transition pore, but was attenuated by genipin and purine nucleotides, antagonists of cloned uncoupling proteins. Knocking out DJ-1, a gene associated with an early onset form of PD, down-regulated the expression of two uncoupling proteins (UCP4, 5), 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 PD.

Fermentation and alternative respiration compensate for NADH dehydrogenase deficiency in a prokaryotic model of DJ-1-associated Parkinsonism

“…Whereas in bacteria a decrease in the proton motive force occurs by the use of alternative respiratory chains, in eukaryotic cells this is mediated by uncoupling proteins. Interestingly, underexpression of uncoupling proteins 4 and 5 in DJ-1-deficient cells results in defective uncoupling and the overproduction of reactive oxygen species (Guzman et al, 2010).…”

“…The crystal structures of YajL and DJ-1 are strikingly similar (Wilson et al, 2003(Wilson et al, , 2005, and their backbone structures are essentially identical (0.9 Å C a root-mean-square deviation), suggesting that they have similar functions. DJ-1 is involved in the cellular response to oxidative stress, and has been suggested to function as a weak protease (Lee et al, 2003), an oxidative stress-activated chaperone Shendelman et al, 2004;Zhou et al, 2006), an atypical peroxiredoxin-like peroxidase (Andres-Mateos et al, 2007;Canet-Avilés et al, 2004), a stabilizer of the antioxidant transcriptional regulator Nrf2 (Clements et al, 2006), an apoptosis inhibitor via interaction with Daxx (Junn et al, 2005), a transcriptional or translational regulator of gene expression (Cookson, 2005; van der Brug et al, 2008) and a regulator of uncoupling protein expression affecting the production of reactive oxygen species (Guzman et al, 2010).…”

The endocannabinoid system in normal and pathological brain ageing

“…In mouse models of AD, signs of oxidative stress also preceded the appearance of learning and memory deficits [77][78][79] further supporting the hypothesis about the potential causal role of oxidative damage in AD. Enhanced oxidative stress was found in the dopaminergic neurons in the ageing substantia nigra of humans suffering from Parkinson's disease [80,81] and in the noradrenergic neurons in the locus coeruleus of AD patients [82]. The selective loss of neurons in these cases is probably the result of the increased ROS production owing to the metabolism of catecholamines [83].…”

Consequences of DJ-1 upregulation following p53 loss and cell transformation

“…DJ-1 (CAP1/RS/PARK7) is a protein described as a protector against oxidative stress in neurons, and is largely documented for its association with Parkinson's disease (Kahle et al, 2009;Aleyasin et al, 2010;Giaime et al, 2010;Guzman et al, 2010;Hao et al, 2010). DJ-1 is also referred to as an oncogene and found to be overexpressed in many types of tumors (Hinkle et al, 2011).…”