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

Research output: Contribution to journalArticle

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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

Fingerprint

Rotenone
Aldehyde Dehydrogenase
Parkinsonian Disorders
Neuroprotective Agents
Animal Models
Dopaminergic Neurons
Poisons
Substantia Nigra
Parkinson Disease
Cell Death
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
Mitochondrial Membrane Potential
Monoamine Oxidase
Tyrosine 3-Monooxygenase
Therapeutic Uses
Aldehydes
Cultured Cells
Dopamine
Mitochondria
Oxidative Stress

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)

Cite this

Neuroprotective effects of aldehyde dehydrogenase 2 activation in rotenone-induced cellular and animal models of parkinsonism. / Chiu, Ching Chi; Yeh, Tu Hsueh; Lai, Szu Chia; Wu-Chou, Yah Huei; Chen, Che Hong; Mochly-Rosen, Daria; Huang, Yin Cheng; Chen, Yu Jie; Chen, Chao Lang; Chang, Ya Ming; Wang, Hung Li; Lu, Chin Song.

In: Experimental Neurology, Vol. 263, 01.01.2015, p. 244-253.

Research output: Contribution to journalArticle

Chiu, CC, Yeh, TH, Lai, SC, Wu-Chou, YH, Chen, CH, Mochly-Rosen, D, Huang, YC, Chen, YJ, Chen, CL, Chang, YM, Wang, HL & Lu, CS 2015, 'Neuroprotective effects of aldehyde dehydrogenase 2 activation in rotenone-induced cellular and animal models of parkinsonism', Experimental Neurology, vol. 263, pp. 244-253. https://doi.org/10.1016/j.expneurol.2014.09.016
Chiu, Ching Chi ; Yeh, Tu Hsueh ; Lai, Szu Chia ; Wu-Chou, Yah Huei ; Chen, Che Hong ; Mochly-Rosen, Daria ; Huang, Yin Cheng ; Chen, Yu Jie ; Chen, Chao Lang ; Chang, Ya Ming ; Wang, Hung Li ; Lu, Chin Song. / Neuroprotective effects of aldehyde dehydrogenase 2 activation in rotenone-induced cellular and animal models of parkinsonism. In: Experimental Neurology. 2015 ; Vol. 263. pp. 244-253.
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