Abstract
Many studies have shown that mitochondrial aldehyde dehydrogenase 2 (ALDH2) functions as a cellular protector against oxidative stress by detoxification of cytotoxic aldehydes. Within dopaminergic neurons, dopamine is metabolized by monoamine oxidase to yield 3,4-dihydroxyphenylacetaldehyde (DOPAL) then converts to a less toxic acid product by ALDH. The highly toxic and reactive DOPAL has been hypothesized to contribute to the selective neurodegeneration in Parkinson's disease (PD). In this study, we investigated the neuroprotective mechanism and therapeutic effect of ALDH2 in rotenone models for parkinsonism. Overexpression of wild-type ALDH2 gene, but not the enzymatically deficient mutant ALDH2*2 (E504K), reduced rotenone-induced cell death. Application of a potent activator of ALDH2, Alda-1, was effective in protecting against rotenone-induced apoptotic cell death in both SH-SY5Y cells and primary cultured substantia nigra (SN) dopaminergic neurons. In addition, intraperitoneal administration of Alda-1 significantly reduced rotenone- or MPTP-induced death of SN tyrosine hydroxylase (TH)-positive dopaminergic neurons. The attenuation of rotenone-induced apoptosis by Alda-1 resulted from decreasing ROS accumulation, reversal of mitochondrial membrane potential depolarization, and inhibition of activation of proteins related to mitochondrial apoptotic pathway. The present study demonstrates that ALDH2 plays a crucial role in maintaining normal mitochondrial function to protect against neurotoxicity and that Alda-1 is effective in ameliorating mitochondrial dysfunction and inhibiting mitochondria-mediated apoptotic pathway. These results indicate that ALDH2 activation could be a neuroprotective therapy for PD.
Highlights
Parkinson’s disease (PD) is the second most common neurodegenerative disorders, which affects 1 to 2% of the population above 65 years of age, and characterized by resting tremors, muscle rigidity, bradykinesia and postural abnormalities (Lees et al, 2009, Olanow et al, 2009)
Subcellular distribution of aldehyde dehydrogenase 2 (ALDH2) protein was analyzed, and Western blot analysis using anti-FLAG antibody showed that WT or mutant (E504K) ALDH2 were selectively expressed in the mitochondrial fraction of stable clones (Fig. 1A)
This study shows that increased ALDH2 activity by either genetic overexpression or pharmacological activation is effective to protect against rotenone-induced cell death
Summary
Parkinson’s disease (PD) is the second most common neurodegenerative disorders, which affects 1 to 2% of the population above 65 years of age, and characterized by resting tremors, muscle rigidity, bradykinesia and postural abnormalities (Lees et al, 2009, Olanow et al, 2009). Mitochondrial dysfunction and subsequent oxidative stress result in the generation of reactive oxygen species (ROS) These processes contribute to neurodegeneration via lipid peroxidation, which lead to the production of reactive aldehydes, such as 3,4-dihydroxyphenylacetaldehyde (DOPAL), malondialdehyde (MDA), and 4-hydroxy-2-nonenal (4-HNE) (Ohta et al, 2004, Marchitti et al, 2007). The presence of 4-HNE is increased in brain tissue in neurodegenerative disorders such as Alzheimer’s disease (AD), Amyotrophic lateral sclerosis (ALS), and PD (Zarkovic, 2003). These reactive aldehydes are neurotoxic and form adducts with proteins, leading to neuronal death in PD
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