Attenuation of MPTP-induced neurotoxicity and behavioural impairment in NSE-XIAP transgenic mice

Abstract

X-linked IAP protein is a potent inhibitor of cell death. Here, we describe a novel transgenic mouse in which the human XIAP gene is expressed under the control of the neuron-specific enolase promoter (NSE-xiap). We demonstrate that nigrostriatal dopamine neurons of NSE-xiap mice were resistant to the damaging effects of the dopaminergic neurotoxin MPTP. MPTP-induced reduction of striatal dopamine metabolism was also attenuated in NSE-xiap mice. Furthermore, NSE-xiap mice treated with MPTP did not exhibit deficits in exploratory behaviour in an open-field test. Taken together, these findings suggest that strategies to enhance neuronal expression of XIAP may provide therapeutic benefit for the treatment of neurodegeneration in Parkinson’s disease.

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopamine neurons in the substantia nigra pars compacta (SNc) leading to depletion of dopamine levels in the striatum (Hornykiewicz and Kish, 1986). The concomitant reduction of dopamine neurotransmitter release results in profound functional deficits in the basal ganglia. As a result, parkinsonian patients develop symptoms such as tremor, muscular rigidity, akinesia, and bradykinesia (a slowness in initiating and executing movements). Current dopamine mimetic-based strategies for treating Parkinson’s disease, such as L-Dopa and dopamine receptor agonists, seek to replenish dopamine levels or emulate the effects of this catecholamine in the striatum. Unfortunately, current dopamine replacement therapies fail to halt the processes responsible for the progressive neurodegeneration in Parkinson’s disease. Hence, identifying biochemical strategies that prevent the degeneration of dopamine neurons may yield a superior therapeutic approach for the treatment of PD.

The molecular signals that mediate the progressive loss of nigral dopamine neurons are not well defined. Administration of the meperidine analog, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) produces a clinical syndrome which resembles PD in humans (Langston et al., 1983). Since MPTP can also recapitulate the principal hallmarks associated with neurodegeneration of the nigrostriatal dopamine pathway in nonhuman primates and certain species of rodents, administration of MPTP is considered a practical and useful experimental model for studying the pathogenesis in PD.

X-linked IAP (XIAP) protein is a mammalian member of the evolutionarily conserved inhibitor of apoptosis (IAP) protein family Deveraux and Reed 1999, Miller 1999, Huang et al 2000. Enhanced expression of mammalian IAP proteins have been reported to attenuate cell death induced by a variety of triggers in vitro Liston et al 1996, LaCasse et al 1998, Deveraux and Reed 1999, and to promote neuronal survival in in vivo models of neurodegeneration Xu et al 1997b, Xu et al 1999, Eberhardt et al 2000, Kugler et al 2000, Perrelet et al 2000, Perrelet et al 2002, Crocker et al 2001b. All previous studies examining the role of IAP protein overexpression have been performed using viral vectors where the specific effects of enhanced expression of an IAP protein in a defined neuronal population could not be distinguished from the potentially beneficial effects resulting from IAP overexpression in surrounding nonneuronal cell types. In resolution of this shortcoming, we describe a novel transgenic mouse in which elevated neuronal expression of XIAP is driven by the neuron-specific enolase (NSE) promoter (Schmecel and Marangos, 1983). In this study, we show that elevated XIAP expression in NSE-xiap mice mitigates the cellular and behavioural deficits produced by MPTP-induced dopaminergic neurodegeneration.