Neuroprotective effects of aldehyde dehydrogenase 2 activation in rotenone-induced cellular and animal models of parkinsonism

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.

Investigation into experimental toxicological properties of plant protection products having a potential link to Parkinson's disease and childhood leukaemia†

“…In response to DNA damage, phosphatidylinositol-3 kinase-related kinases ATM (ataxia telangiectasia mutated) and ATR (ATM-and Rad3-related) are initially activated and subsequently phosphorylate a variety of proteins that regulate the DNA-damage response. DNA DSBs observed in some studies with chlorpyrifos and atrazine may be due to the ability of these compounds to generate highly reactive molecules/radicals (Huang et al, 2015;. Aldicarb has caused a dosedependent DNA damage, with single-strand breaks being produced by low concentrations during short time, which could be repaired, whereas high concentration led to DSBs which were difficult to repair .…”

“…The present study demonstrates that rotenone or MPP+ induces DA neurotoxicity through oxidative stress. Moreover, Alda-1 is effective in ameliorating mitochondrial dysfunction by inhibiting rotenone-or MPP+-induced mitochondria-mediated oxidative stress that leads to apoptosis (Chiu et al, 2015).…”

“…NDI1-transducted SK-N-MC cells expressing the rotenoneinsensitive single subunit NADH dehydrogenase of yeast (NDI1) that acts as a replacement for the entire CI in mammalian cells were completely resistant to 100 nM rotenone-mediated cell death (at 48 h of exposure) indicating that rotenone -induced toxicity requires rotenone biding of CI . In all rotenone models, mitochondria CI is inhibited at the dose that cause neurodegeneration KE2 Mitochondrial dysfunction Strong Rationale: Many studies showing that antioxidants protect the cells against rotenone or MPTP induced oxidative stress are published (Wu et al, 1994;Saravanan et al, 2006;Tseng et al, 2014;Chiu et al, 2015;Nataraj et al, 2015). This provides (indirect) evidence for essentiality of KE2, if production of ROS is assumed as direct consequence/sign of mitochondrial dysfunction.…”

Integrated High-Content Quantification of Intracellular ROS Levels and Mitochondrial Morphofunction

“…When generated at low levels, 4-HNE can interact with signaling targets, including JNK, P38 MAPK, cell cycle regulators, PKCβ, and PKCδ, leading to numerous cellular responses, ranging from increased expression of the antioxidant enzyme TRXR1 to irreversible cytotoxic injuries and cell death (Chen et al 2005;Riahi et al 2010). Mitochondrial aldehyde dehydrogenase 2 (ALDH2) can protect against oxidative stress by detoxification of these cytotoxic aldehydes (Chiu et al 2015). ROS can react covalently with certain atomic elements in biological macromolecules ( Fig.…”

Two-Step Induction of Dopaminergic Neurone Differentiation of Leukapharesis-Derived Mesenchymal Stem Cells

“…The disease is caused by the loss of midbrain dopamine neurons resulting in decrease in striatal dopamine (2). The worldwide prevalence of PD ranges from 57 to 230 per 100,000 persons (3).…”