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

Ching Chi Chiu, Tu Hsueh Yeh, Szu Chia Lai, Yah Huei Wu-Chou, Che Hong Chen, Daria Mochly-Rosen, Yin Cheng Huang, Yu Jie Chen, Chao Lang Chen, Ya Ming Chang, Hung Li Wang, Chin Song Lu

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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.

Original languageEnglish
Pages (from-to)244-253
Number of pages10
JournalExperimental Neurology
Volume263
DOIs
Publication statusPublished - Jan 1 2015
Externally publishedYes

Keywords

  • Alda-1
  • Aldehyde dehydrogenase 2 (ALDH2)
  • Mitochondrial dysfunction
  • Parkinson's disease
  • Rotenone
  • Substantia nigra dopaminergic neurons

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience
  • Medicine(all)

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    Chiu, C. C., Yeh, T. H., Lai, S. C., Wu-Chou, Y. H., Chen, C. H., Mochly-Rosen, D., Huang, Y. C., Chen, Y. J., Chen, C. L., Chang, Y. M., Wang, H. L., & Lu, C. S. (2015). Neuroprotective effects of aldehyde dehydrogenase 2 activation in rotenone-induced cellular and animal models of parkinsonism. Experimental Neurology, 263, 244-253. https://doi.org/10.1016/j.expneurol.2014.09.016