Modulation of Aldehyde Dehydrogenase Activity Affects (±)-4-Hydroxy-2E-nonenal (HNE) Toxicity and HNE–Protein Adduct Levels in PC12 Cells

Abstract

Oxidative stress is known to be one of the major factors underlying Parkinson's disease (PD). One of the consequences of oxidative stress is lipid peroxidation. A toxic product of lipid peroxidation, (±)-4-hydroxy-2E-nonenal (HNE) leads to membrane disruption and formation of HNE-protein adducts and such adducts have been detected in PD brain tissues. Aldehyde dehydrogenases (ALDHs) are involved in metabolizing HNE and other endogenous aldehydes. Interestingly, the cytosolic aldehyde dehydrogenase 1A1 (ALDH1A1) has been reported to be down-regulated in brain tissues affected in PD which could result in enhancement of HNE toxicity. We sought to first establish the role of ALDH1A1 in mediating HNE toxicity in PC12 cells by overexpressing ALDH1A1 and by using disulfiram, an ALDH inhibitor. Overexpression and inhibition of ALDH1A1 activity resulted in reduced and increased HNE toxicity, respectively. We then established conditions for detecting HNE-protein adducts following HNE treatment and showed that overexpression and inhibition of ALDH activity resulted in reduced and increased formation of HNE-protein adducts, respectively. We also show that 6-methyl-2-(phenylazo)-3-pyridinol, previously identified as an activator of ALDH1A1, can protect PC12 cells against HNE-mediated toxicity and can cause a small but significant decrease in levels of HNE-protein adducts. Our results should encourage identification of more potent ALDH activators and their testing in the PC12-HNE model. Such cytoprotective compounds could then be tested for their neuroprotective activity in in vivo models of oxidative stress-induced PD.

Cell death and diseases related to oxidative stress:4-hydroxynonenal (HNE) in the balance

“…They can be downregulated in some disorders such as Parkinson disease. The recent study by Kong et al 144 shows that ALDH1A1 is a major HNE-detoxification enzyme in PC12 cells. Its overexpression results in reduced HNE toxicity, and its inhibition is neurotoxic, with a high accumulation of HNEprotein adducts.…”

Aldehyde dehydrogenase 1 defines and protects a nigrostriatal dopaminergic neuron subpopulation

“…Moreover, the presence of extra ALDH1A1 effectively rescued the loss of DA neurons derived from A53T transgenic mice ( Figure 7C). In addition, an ALDH1A1 activator, 6-methyl-2-phenylazo-3-pyridinol (SIB1757) (26), also significantly improved the survival of TH-positive neurons in A53T cultures ( Figure 7D). Together, these observations provide direct support for a protective function of ALDH1A1 in maintenance of the survival of midbrain DA neurons against α-synuclein-induced cytotoxicity.…”

Aldehyde dehydrogenase (ALDH) in Alzheimer’s and Parkinson’s disease

“…Moreover, they could show that this was linked to the fact that decrease or increased HNE-protein adducts were formed, respectively. Additionally, 6-methyl-2-(phenylazo)-3-pyridinol, an activator of ALDH1A1, demonstrated cytoprotective effects in PC12 cells (Kong and Kotraiah 2012). At the same line as Zhang and colleagues, Bai and Mei reported neuroprotective effects of overexpression of the mitochondrial ALDH2 against HNE neurotoxicity (Bai and Mei 2011).…”

“…reduced accumulation of protein-HNE adducts and reduced expression of caspase-3, an apoptotic marker (Zhang et al 2010), points to the importance of ALDH activity in cell survival. Similarly, Kong and Kotraiah demonstrated that overexpressing ALDH1A1 in PC12 cells increased HNE toxicity, while inhibiting ALDH1A1 by disulfiram reduced its toxicity (Kong and Kotraiah 2012). Moreover, they could show that this was linked to the fact that decrease or increased HNE-protein adducts were formed, respectively.…”