Neurochemical and motor changes in mice with combined mutations linked to Parkinson's disease.

Xiang Bai,Chao Shi,Paul Anthony Martinez,Margaret Chia-Ying Wey,Elizabeth Fernandez,Randy Strong

doi:10.1080/20010001.2017.1267855

Abstract

ABSTRACTConsiderable evidence suggests that oxidative stress plays a role in the pathogenesis of Parkinson’s disease (PD), the most prevalent neurodegenerative movement disorder. Reduced expression of aldehyde dehydrogenase-1 (ALDH1) and glutathione peroxidase-1 (GPX1), enzymes that function to detoxify aldehydes and hydroxyl radicals, respectively, has been reported in the substantia nigra of patients who died with PD. To determine whether deficiency in these two genes contributes to the pathogenesis of PD, mice were generated with homozygous null mutations of both Aldh1a1 (the murine homolog of ALDH1) and Gpx1 genes [knockout (KO) mice]. At 6 and 18 months of age, KO mice showed a significantly decreased latency to fall in the automated accelerating rotarod test and increased time to complete the pole test opamine levels were not altered; however, the dopamine metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) and the DOPAC/dopamine ratio were significantly reduced at 18 months of age. Proteins adducted with 4-hydroxynonenal, the end-product of lipid peroxidation, were increased in the. midbrain and striatum of KO mice at 6 and 18 months. In conclusion, dual mutations in Gpx1 and Aldh1a1 genes are associated with motor deficits and increased lipid peroxidation in adult mice.

Highlights

Parkinson’s disease (PD) is the second most prevalent age-related neurodegenerative disorder, after Alzheimer’s disease, affecting up to 5% of the population aged 65–85 years
We found that mice deficient in both Glutathione peroxidase-1 (Gpx1) and Aldh1a1 exhibited increased 4-HNE, reduced 3,4-dihydroxyphenylacetic acid (DOPAC)/ dopamine ratios, and motor deficits
Expression of aldehyde dehydrogenase-1 (ALDH1) and glutathione peroxidase-1 (GPX1), gene products that are important for the clearance of aldehydes and free radicals, respectively, was reported to be reduced in the substantia nigra (SN) of PD patients, suggesting that ALDH1 and GPX1 play important roles in the pathogenesis of PD [4,14]

Summary

Introduction

Parkinson’s disease (PD) is the second most prevalent age-related neurodegenerative disorder, after Alzheimer’s disease, affecting up to 5% of the population aged 65–85 years. A large amount of evidence suggests that oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases including PD [1]. Glutathione peroxidase (GPX) is a key enzyme in removing free radicals in vivo. It protects cells against oxidative damage by oxidizing glutathione to glutathione disulfide. GPX1, the most abundant form of GPX, plays a crucial role in protecting cells against oxidative damage by decreasing the production of reactive hydroxyl radicals [3]. 4-hydroxynonenal (4-HNE) is elevated in the brains of patients who had PD [8] Both DOPAL and 4-HNE are toxic to dopaminergic cells in vitro and in vivo [6,9,10,11,12]. The cytosolic aldehyde dehydrogenase ALDH1 is and richly expressed in dopaminergic neurons in the SN [13,14,15] and its mRNA expression is significantly decreased in surviving dopaminergic

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