Mitochondrial dysfunction in the striatum of aged chronic mouse model of Parkinson’s disease

Gaurav Patki

doi:10.3389/neuro.24.003.2009

Abstract

Mitochondrial oxidative stress and dysfunction has been implicated as a possible mechanism for the onset and progression of Parkinson-like neurodegeneration. However, long-term mitochondrial defects in chronic animal neurodegenerative models have not been demonstrated. In this study, we investigated the function of striatal mitochondria 6 weeks after the induction of a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (MPD). Although severe depression of mitochondrial respiration was observed immediately after acute administrations of MPTP, we failed to detect a significant mitochondrial inhibition in presence of striatal dopamine (DA) deficit 6 weeks after the chronic MPD induction in young adult mice. In contrast, when aged mice were chronically treated with MPTP and at 6 weeks post-treatment, these animals suffered an inhibition of the basal (state 4) and adenosine 5′-diphosphate-stimulated (state 3) respiration and a fall in adenosine triphosphate level in the striatal mitochondria. The aged chronic MPD also brought about a sustained diminution of striatal anti-oxidant enzyme levels including that of superoxide dismutases and cytochrome c. The mitochondrial deficits in the striatum of aged chronic MPD 6 weeks after treatment were further correlated with significant losses of striatal DA, tyrosine hydroxylase, DA uptake transporter, and with impaired movement when tested on a challenging beam. Our findings suggest that MPTP may trigger the neurodegenerative process by obstructing the mitochondrial function; however, striatal mitochondria in young animals may potentially rejuvenate, whereas mitochondrial dysfunction is sustained in the aged chronic MPD. Therefore, the aged chronic MPD may serve as a suitable investigative model for further elucidating the integral relationship between mitochondrial dysfunction and neurodegenerative disorder, and for assessing the therapeutic efficacy of mitochondrial protective agents as potential neuroprotective drugs.

Highlights

Mitochondria are dynamic organelles that are present in all mammalian cells
48.3% dihydroxyphenylacetic acid (DOPAC) in the striatum 2 h later (Table 1). These results indicate that MPTP has an acute effect in depleting the vesicular DA stores; and when administered chronically with probenecid, MPTP produces a persistent loss of DA in the striatum
In summary, the present study examined the role of striatal mitochondrial function in the chronic model of Parkinson’s disease (MPD)

Summary

Introduction

Mitochondria are dynamic organelles that are present in all mammalian cells. They are functionally well known for generating adenosine triphosphate (ATP) as the source of energy, for sequestering excess cytoplasmic Ca++, for producing and disposing of reactive superoxide free radicals, and for supporting cell survival and preventing cell death (Chan, 2006). The generation of ATP by mitochondria involves oxidative phosphorylation of a number of protein complexes within the electron transport chain system located in the inner mitochondrial membrane. A number of mitochondrial anti-oxidant enzymes such as the superoxide dismutase (SOD) and cytochrome c can scavenge any Abbreviations: ADP, adenosine 5′-diphosphate; ATP, adenosine triphosphate; DA, dopamine; DAT, dopamine uptake transporter; DOPAC, 3,4-dihydroxyphenylacetic acid; GAPDH, glyceraldehyde 3 phosphate dehydrogenase; MPD, mouse model of Parkinson’s disease; mtDNA, mitochondrial DNA; MPTP, 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson’s disease; ROS, reactive oxygen species; SOD, superoxide dismutase; TH, tyrosine hydroxylase

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