| First Author | Yeung PKK | Year | 2017 |
| Journal | Neurobiol Aging | Volume | 50 |
| Pages | 119-133 | PubMed ID | 27960106 |
| Mgi Jnum | J:239840 | Mgi Id | MGI:5881859 |
| Doi | 10.1016/j.neurobiolaging.2016.11.008 | Citation | Yeung PKK, et al. (2017) Aldose reductase deficiency leads to oxidative stress-induced dopaminergic neuronal loss and autophagic abnormality in an animal model of Parkinson's disease. Neurobiol Aging 50:119-133 |
| abstractText | 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. |
