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, 2017 02.
Article
in En
| MEDLINE
| ID: mdl-27960106
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 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Parkinson Disease
/
Autophagy
/
Aldehyde Reductase
/
Oxidative Stress
/
Dopaminergic Neurons
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Neurobiol Aging
Year:
2017
Document type:
Article
Affiliation country:
China