Uncoupling protein 2 protects dopaminergic neurons from acute 1,2,3,6‐methyl‐phenyl‐tetrahydropyridine toxicity

Abstract

Oxidative stress is implicated in the death of dopaminergic neurons in sporadic forms of Parkinson's disease. Because oxidative stress can be modulated endogenously by uncoupling proteins (UCPs), we hypothesized that specific neuronal expression of UCP2, one member of the UCP family that is rapidly induced in the CNS following insults, could confer neuroprotection in a mouse model of Parkinson's disease. We generated transgenic mice overexpressing UCP2 in catecholaminergic neurons under the control of the tyrosine hydroxylase promoter (TH-UCP2). In these mice, dopaminergic neurons of the substantia nigra showed a twofold elevation in UCP2 expression, elevated uncoupling of their mitochondria, and a marked reduction in indicators of oxidative stress, an effect also observed in the striatum. Upon acute exposure to 1,2,3,6-methyl-phenyl-tetrahydropyridine, TH-UCP2 mice showed neuroprotection and retention of locomotor functions. Our data suggest that UCP2 may represent a drug target for slowing the progression of Parkinson's disease.

Uncoupling protein-2 up-regulation and enhanced cyanide toxicity are mediated by PPARα activation and oxidative stress

“…It is widely accepted that constitutive expression of UCP-2 can produce neuro-protection by uncoupling oxidative phosphorylation to reduce mitochondrial ROS generation (Horvath et al, 2003;Conti et al, 2005). We have shown in primary cortical cells that Wy14,643 can induce UCP-2 up-regulation and switch cyanide-induced apoptosis to necrosis .…”

Protective properties afforded by pioglitazone against intrastriatal LPS in Sprague–Dawley rats

“…Therefore, since the main physiological role of UCP2 is to lower reactive oxygen species production [7,13] UPC2 expression might be increased as a compensatory response to the inflammation and oxidative stress that follows LPS injection. Support for this concept comes from evidence that suggests UCP2 is involved in neuroprotection against a PD model [1,10], where deletion of UCP2 enhanced the susceptibility of dopaminergic neurons towards cell death [2]. However, in this case UCP2 over-expression may be detrimental to the cell as exacerbated uncoupling could result in mitochondrial impairment.…”

“…Biologically active substances like LPS affect the transcription, translation, and/or activity of UCP2 [15]. In addition, UCP2 may be involved in PD [1,10] and PPAR-γ agonists can increase its expression [23]. For a detailed review on UCP2 and its function, see Mattiasson and Sullivan 2006 [24].…”

Mitochondrial dysfunction in human pathologies

“…UCP-2 over-expression also reduces lipid peroxidation at least in the brain (75), where it protects neurons against seizure and neuronal damage (76,77). Over-expression in dopaminergic neurons protects from Parkinson-inducing agents (78). Furthermore, increased expression of human UCP-2 in the adult fly nervous system extends fly life span (77).…”