Aldose reductase deficiency leads to oxidative stress-induced dopaminergic neuronal loss and autophagic abnormality in an animal model of Parkinson's disease

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• 作者：Patrick K.K. Yeung^a ; Angela K.W. Lai^a ; Hyo Jin Son^b ; Xu Zhang^a ; Onyou Hwang^b ; Stephen S.M. Chung^c ; Sookja K. Chung^a ; ^d ; ^{skchung@hkucc.hku.hk}
• 关键词：Parkinson's disease ; Aldose reductase ; Knockout mice ; Oxidative stress
• 刊名：Neurobiology of Aging
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：50
• 期：Complete
• 页码：119-133
• 全文大小：3643 K
• 卷排序：50

文摘

Fungicide exposure causes degeneration of dopaminergic neurons and contributes to Parkinson's disease (PD). Benomyl inhibits enzymes responsible for detoxifying the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde. Aldose reductase (AR) is known as tetrahydrobiopterin (BH4) reductase that generates BH4, a cofactor for tyrosine hydroxylase (TH) involved in dopamine synthesis. AR also acts as an aldehyde reductase involved in detoxifying 3,4-dihydroxyphenylacetaldehyde. In PD patients, the level of AR is significantly lower in the cerebellum. To determine if AR deficiency contributes to PD, AR wild-type (AR+/+) and knockout (AR−/−) mice were administrated with 1-methyl-4-phenyl -1,2,3,6- tetrahydropyridine (MPTP). The MPTP-treated AR−/− mice showed more severe behavioral deficits and brain damage than that of AR+/+ mice. Contrary to expectation, under normal or MPTP-treated condition, AR−/− mice showed a significant elevation of BH4 and dopamine in the midbrain, suggesting that either AR does not contribute to BH4 production, or other BH4 synthetic pathways are induced. The AR−/− brain showed upregulation of peroxynitrite, inducible nitric oxide synthase and downregulation of antioxidant enzymes, Cu/Zn superoxide dismutase (SOD) and peroxiredoxin 2 (Prx2), which indicate an increase in oxidative stress. In line with the animal data, pretreating the SH-SY5Y cells with AR inhibitors (Fidarestat or Epalrestat) before MPP+ treatment, increased severe cell death and mitochondrial fragmentation with downregulation of SOD were observed when compared to the MPP+ treatment alone. Cycloxygenase 2 (COX2), which can lead to the oxidation of dopamine, was upregulated in AR−/− brains. Autophagic proteins, beclin-1 and LC3B were also downregulated. The loss of dopaminergic neurons was associated with activation of p-ERK1/2. These findings suggest that AR plays an important role in protecting dopaminergic neuron against neurotoxic metabolites in PD.