title: Aldose reductase deficiency leads to oxidative stress-induced dopaminergic neuronal loss and autophagic abnormality in an animal model of Parkinson's disease.
abstract: 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 BH4and dopamine in the midbrain, suggesting that either AR does not contribute to BH4production, or other BH4synthetic 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.
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Patrick K K
authors.initials: PKK
authors.lastname: Yeung
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Angela K W
authors.initials: AKW
authors.lastname: Lai
authors.affiliation: Department of Biochemistry, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Hyo Jin
authors.initials: HJ
authors.lastname: Son
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Xu
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Onyou
authors.initials: O
authors.lastname: Hwang
authors.affiliation: Division of Science and Technology, United International College, Zhuhai, Guandong, China.
authors.forename: Stephen S M
authors.initials: SSM
authors.lastname: Chung
authors.affiliation: School of Biomedical Sciences, The University of Hong Kong, Hong Kong SAR, China; Research Center of Heart, Brain, Hormone and Healthy Aging, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. Electronic address: skchung@hkucc.hku.hk.
authors.forename: Sookja K
authors.initials: SK
authors.lastname: Chung
mesh_terms: D000449:Aldehyde Reductase / Q000172:deficiency*; D000818:Animals; D001343:Autophagy; D002478:Cells, Cultured; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000473:pathology*; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress / Q000502:physiology*; D010300:Parkinson Disease / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology
chemical_list: D000449:Aldehyde Reductase
keywords: Aldose reductase; Knockout mice; Oxidative stress; Parkinson's disease