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

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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.

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          Most cited references 34

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          Parkinson's disease.

           Bobby Thomas,  M. Beal (2007)
          Parkinson's disease (PD) is a chronic progressive neurodegenerative movement disorder characterized by a profound and selective loss of nigrostriatal dopaminergic neurons. Clinical manifestations of this complex disease include motor impairments involving resting tremor, bradykinesia, postural instability, gait difficulty and rigidity. Current medications only provide symptomatic relief and fail to halt the death of dopaminergic neurons. A major hurdle in development of neuroprotective therapies are due to limited understanding of disease processes leading to death of dopaminergic neurons. While the etiology of dopaminergic neuronal demise is elusive, a combination of genetic susceptibilities and environmental factors seems to play a critical role. The majority of PD cases are sporadic however, the discovery of genes linked to rare familial forms of disease (encoding alpha-synuclein, parkin, DJ-1, PINK-1 and LRRK2) and studies from experimental animal models has provided crucial insights into molecular mechanisms in disease pathogenesis and identified probable targets for therapeutic intervention. Recent findings implicate mitochondrial dysfunction, oxidative damage, abnormal protein accumulation and protein phosphorylation as key molecular mechanisms compromising dopamine neuronal function and survival as the underlying cause of pathogenesis in both sporadic and familial PD. In this review we provide an overview of the most relevant findings made by the PD research community in the last year and discuss how these significant findings improved our understanding of events leading to nigrostriatal dopaminergic degeneration, and identification of potential cell survival pathways that could serve as targets for neuroprotective therapies in preventing this disabling neurological illness.
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            Parkinson disease: from pathology to molecular disease mechanisms.

            Parkinson disease (PD) is a complex neurodegenerative disorder with both motor and nonmotor symptoms owing to a spreading process of neuronal loss in the brain. At present, only symptomatic treatment exists and nothing can be done to halt the degenerative process, as its cause remains unclear. Risk factors such as aging, genetic susceptibility, and environmental factors all play a role in the onset of the pathogenic process but how these interlink to cause neuronal loss is not known. There have been major advances in the understanding of mechanisms that contribute to nigral dopaminergic cell death, including mitochondrial dysfunction, oxidative stress, altered protein handling, and inflammation. However, it is not known if the same processes are responsible for neuronal loss in nondopaminergic brain regions. Many of the known mechanisms of cell death are mirrored in toxin-based models of PD, but neuronal loss is rapid and not progressive and limited to dopaminergic cells, and drugs that protect against toxin-induced cell death have not translated into neuroprotective therapies in humans. Gene mutations identified in rare familial forms of PD encode proteins whose functions overlap widely with the known molecular pathways in sporadic disease and these have again expanded our knowledge of the neurodegenerative process but again have so far failed to yield effective models of sporadic disease when translated into animals. We seem to be missing some key parts of the jigsaw, the trigger event starting many years earlier in the disease process, and what we are looking at now is merely part of a downstream process that is the end stage of neuronal death. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Targeting aldehyde dehydrogenase 2: new therapeutic opportunities.

              A family of detoxifying enzymes called aldehyde dehydrogenases (ALDHs) has been a subject of recent interest, as its role in detoxifying aldehydes that accumulate through metabolism and to which we are exposed from the environment has been elucidated. Although the human genome has 19 ALDH genes, one ALDH emerges as a particularly important enzyme in a variety of human pathologies. This ALDH, ALDH2, is located in the mitochondrial matrix with much known about its role in ethanol metabolism. Less known is a new body of research to be discussed in this review, suggesting that ALDH2 dysfunction may contribute to a variety of human diseases including cardiovascular diseases, diabetes, neurodegenerative diseases, stroke, and cancer. Recent studies suggest that ALDH2 dysfunction is also associated with Fanconi anemia, pain, osteoporosis, and the process of aging. Furthermore, an ALDH2 inactivating mutation (termed ALDH2*2) is the most common single point mutation in humans, and epidemiological studies suggest a correlation between this inactivating mutation and increased propensity for common human pathologies. These data together with studies in animal models and the use of new pharmacological tools that activate ALDH2 depict a new picture related to ALDH2 as a critical health-promoting enzyme.
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                Author and article information

                Journal
                0370712
                3660
                Exp Neurol
                Exp. Neurol.
                Experimental neurology
                0014-4886
                1090-2430
                15 April 2015
                28 September 2014
                January 2015
                01 January 2016
                : 263
                : 244-253
                Affiliations
                [a ]Neuroscience Research Center, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan
                [b ]Section of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan
                [c ]Healthy Aging Research Center, College of Medicine, Chang Gung University, Taoyuan, Taiwan
                [d ]College of Medicine, Chang Gung University, Taoyuan, Taiwan
                [e ]Human Molecular Genetics Laboratory, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan
                [f ]Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA
                [g ]Department of Neurosurgery, Chang Gung Memorial Hospital at Linkou Medical Center, Taoyuan, Taiwan
                [h ]Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, Taoyuan, Taiwan
                Author notes
                [* ]Corresponding authors: Hung-Li Wang, Ph.D., Professor, Department of Physiology and Pharmacology, College of Medicine, Chang Gung University, No. 259, Wen-Hwa 1 st Road, Kweishan, Taoyuan 333, Taiwan, TEL: +886-3-2118800 ext 5060, FAX: +886-3-2118700, hlwns@ 123456mail.cgu.edu.tw . Chin-Song Lu, M.D., Professor and Director, Neuroscience Research Center, Section of Movement Disorders, Department of Neurology, Chang Gung Memorial Hospital at Linkou Medical Center, No. 5, Fu-Shin Street, Kweishan, Taoyuan, 33305, Taiwan, TEL: +886-3-3281200 ext 8418, FAX: +886-3-3971504, c81214@ 123456adm.cgmh.org.tw ; bob.cslu@ 123456gmail.com
                [#]

                Equal contribution

                Article
                NIHMS660840
                10.1016/j.expneurol.2014.09.016
                4415848
                25263579
                © 2014 Published by Elsevier Inc.

                This manuscript version is made available under the CC BY-NC-ND 4.0 license.

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