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      Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease

      review-article
      a , b , a , b , a , b , c , *
      Redox Biology
      Elsevier
      6-OHDA, 6-hydroxydopamine, the ADAGIO study, the Attenuation of Disease Progression with Azilect Given Once-daily) study , CBZ, carbamazepine, curcumin, (1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, the DATATOP Study, the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism Study , EGCG, epigallocatechin gallate, GSH, glutathione, HIF1α, hypoxia-inducible factor 1-alpha, HNE, 4-hydroxynonenal, iPSC, induced pluripotent stem cells, LRRK2, leucine-rich repeat kinase 2, MDA, malondialdehyde, MnSOD, manganese superoxide dismutase, MitoQ, mitochondrially-targeted coenzyme Q, MPP+, 1-methyl-4-phenylpyridinium, MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine, the NET-PD network, the NINDS Exploratory Trials in Parkinson’s Disease (NET-PD) network, Nrf2, Nuclear factor (erythroid-derived 2)-like 2, PINK1, PTEN-induced putative kinase 1, rasagiline, N-propargyl-1-(R)-aminoindan, ROS/RNS, reactive oxygen and nitrogen species, SOD, superoxide dismutase, Selegiline, N-propargyl-methamphetamine, Sirt1, NAD-dependent deacetylast sirtuin-1, the TEMPO Study, the TVP-1012 in Early Monotherapy for PD Outpatients Study, TFEB, transcription factor EB, UCHL1, ubiquitin carboxyl-terminal hydrolase L1, UPDRS, Unified Parkinson’s Disease Rating Scale, Parkinson’s disease, Protein aggregation, Neurons, Mitochondrial dysfunction, Reactive oxygen species, Anti-oxidants, Autophagy, Toxins, Clinical trials, Animal models, Redox signaling

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          Abstract

          Oxidative stress including DNA damage, increased lipid and protein oxidation, are important features of aging and neurodegeneration suggesting that endogenous antioxidant protective pathways are inadequate or overwhelmed. Importantly, oxidative protein damage contributes to age-dependent accumulation of dysfunctional mitochondria or protein aggregates. In addition, environmental toxins such as rotenone and paraquat, which are risk factors for the pathogenesis of neurodegenerative diseases, also promote protein oxidation. The obvious approach of supplementing the primary antioxidant systems designed to suppress the initiation of oxidative stress has been tested in animal models and positive results were obtained. However, these findings have not been effectively translated to treating human patients, and clinical trials for antioxidant therapies using radical scavenging molecules such as α-tocopherol, ascorbate and coenzyme Q have met with limited success, highlighting several limitations to this approach. These could include: (1) radical scavenging antioxidants cannot reverse established damage to proteins and organelles; (2) radical scavenging antioxidants are oxidant specific, and can only be effective if the specific mechanism for neurodegeneration involves the reactive species to which they are targeted and (3) since reactive species play an important role in physiological signaling, suppression of endogenous oxidants maybe deleterious. Therefore, alternative approaches that can circumvent these limitations are needed. While not previously considered an antioxidant system we propose that the autophagy-lysosomal activities, may serve this essential function in neurodegenerative diseases by removing damaged or dysfunctional proteins and organelles.

          Graphical abstract

          Highlights

          • Significant oxidative damage occurs in neurodegenerative disease brains.

          • Effective in animal models with single toxins, antioxidants are ineffective in clinical trials.

          • The failure of antioxidant therapy maybe due to propagation of cellular damage.

          • Autophagic clearance of diverse damaged molecules may provide antioxidant mechanisms.

          • Further mechanistic and translational studies on autophagy therapy are needed.

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          Most cited references99

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          Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia.

          Autophagy is a process by which cytoplasmic organelles can be catabolized either to remove defective structures or as a means of providing macromolecules for energy generation under conditions of nutrient starvation. In this study we demonstrate that mitochondrial autophagy is induced by hypoxia, that this process requires the hypoxia-dependent factor-1-dependent expression of BNIP3 and the constitutive expression of Beclin-1 and Atg5, and that in cells subjected to prolonged hypoxia, mitochondrial autophagy is an adaptive metabolic response which is necessary to prevent increased levels of reactive oxygen species and cell death.
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            • Article: not found

            Peroxynitrite: biochemistry, pathophysiology and development of therapeutics.

            Peroxynitrite--the product of the diffusion-controlled reaction of nitric oxide with superoxide radical--is a short-lived oxidant species that is a potent inducer of cell death. Conditions in which the reaction products of peroxynitrite have been detected and in which pharmacological inhibition of its formation or its decomposition have been shown to be of benefit include vascular diseases, ischaemia-reperfusion injury, circulatory shock, inflammation, pain and neurodegeneration. In this Review, we first discuss the biochemistry and pathophysiology of peroxynitrite and then focus on pharmacological strategies to attenuate the toxic effects of peroxynitrite. These include its catalytic reduction to nitrite and its isomerization to nitrate by metalloporphyrins, which have led to potential candidates for drug development for cardiovascular, inflammatory and neurodegenerative diseases.
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              • Abstract: found
              • Article: not found

              Trehalose, a novel mTOR-independent autophagy enhancer, accelerates the clearance of mutant huntingtin and alpha-synuclein.

              Trehalose, a disaccharide present in many non-mammalian species, protects cells against various environmental stresses. Whereas some of the protective effects may be explained by its chemical chaperone properties, its actions are largely unknown. Here we report a novel function of trehalose as an mTOR-independent autophagy activator. Trehalose-induced autophagy enhanced the clearance of autophagy substrates like mutant huntingtin and the A30P and A53T mutants of alpha-synuclein, associated with Huntington disease (HD) and Parkinson disease (PD), respectively. Furthermore, trehalose and mTOR inhibition by rapamycin together exerted an additive effect on the clearance of these aggregate-prone proteins because of increased autophagic activity. By inducing autophagy, we showed that trehalose also protects cells against subsequent pro-apoptotic insults via the mitochondrial pathway. The dual protective properties of trehalose (as an inducer of autophagy and chemical chaperone) and the combinatorial strategy with rapamycin may be relevant to the treatment of HD and related diseases, where the mutant proteins are autophagy substrates.
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                Author and article information

                Journal
                Redox Biol
                Redox Biol
                Redox Biology
                Elsevier
                2213-2317
                25 December 2013
                25 December 2013
                2014
                : 2
                : 82-90
                Affiliations
                [a ]Center for Free Radical Biology, University of Alabama at Birmingham, United States
                [b ]Department of Pathology, University of Alabama at Birmingham, United States
                [c ]Department of Veterans Affairs, Birmingham VA Medical Center, United States
                Author notes
                [* ]Corresponding author at: Department of Pathology, University of Alabama at Birmingham, Biomedical Research Building II, 901 19th Street South, Birmingham, AL 35294, United States. Tel.: +205 996 5153; fax: +205 934 7447. zhanja@ 123456uab.edu
                Article
                S2213-2317(13)00101-8
                10.1016/j.redox.2013.12.013
                3909266
                24494187
                c6251b4f-4c02-4d23-85c8-9729040ef0ce
                © 2014 The Authors
                History
                : 13 December 2013
                : 15 December 2013
                : 17 December 2013
                Categories
                Article

                the tempo study, the tvp-1012 in early monotherapy for pd outpatients study,parkinson’s disease,egcg, epigallocatechin gallate,hne, 4-hydroxynonenal,lrrk2, leucine-rich repeat kinase 2,pink1, pten-induced putative kinase 1,6-ohda, 6-hydroxydopamine,curcumin, (1e,6e)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione,cbz, carbamazepine,the datatop study, the deprenyl and tocopherol antioxidative therapy of parkinsonism study,updrs, unified parkinson’s disease rating scale,mptp, 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine,ipsc, induced pluripotent stem cells,autophagy,mnsod, manganese superoxide dismutase,selegiline, n-propargyl-methamphetamine,mda, malondialdehyde,redox signaling,hif1α, hypoxia-inducible factor 1-alpha,clinical trials,protein aggregation,the net-pd network, the ninds exploratory trials in parkinson’s disease (net-pd) network,rasagiline, n-propargyl-1-(r)-aminoindan,animal models,sirt1, nad-dependent deacetylast sirtuin-1,mpp+, 1-methyl-4-phenylpyridinium,sod, superoxide dismutase,the adagio study, the attenuation of disease progression with azilect given once-daily) study,neurons,nrf2, nuclear factor (erythroid-derived 2)-like 2,toxins,tfeb, transcription factor eb,anti-oxidants,gsh, glutathione,ros/rns, reactive oxygen and nitrogen species,mitoq, mitochondrially-targeted coenzyme q,reactive oxygen species,uchl1, ubiquitin carboxyl-terminal hydrolase l1,mitochondrial dysfunction
                the tempo study, the tvp-1012 in early monotherapy for pd outpatients study, parkinson’s disease, egcg, epigallocatechin gallate, hne, 4-hydroxynonenal, lrrk2, leucine-rich repeat kinase 2, pink1, pten-induced putative kinase 1, 6-ohda, 6-hydroxydopamine, curcumin, (1e,6e)-1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, cbz, carbamazepine, the datatop study, the deprenyl and tocopherol antioxidative therapy of parkinsonism study, updrs, unified parkinson’s disease rating scale, mptp, 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine, ipsc, induced pluripotent stem cells, autophagy, mnsod, manganese superoxide dismutase, selegiline, n-propargyl-methamphetamine, mda, malondialdehyde, redox signaling, hif1α, hypoxia-inducible factor 1-alpha, clinical trials, protein aggregation, the net-pd network, the ninds exploratory trials in parkinson’s disease (net-pd) network, rasagiline, n-propargyl-1-(r)-aminoindan, animal models, sirt1, nad-dependent deacetylast sirtuin-1, mpp+, 1-methyl-4-phenylpyridinium, sod, superoxide dismutase, the adagio study, the attenuation of disease progression with azilect given once-daily) study, neurons, nrf2, nuclear factor (erythroid-derived 2)-like 2, toxins, tfeb, transcription factor eb, anti-oxidants, gsh, glutathione, ros/rns, reactive oxygen and nitrogen species, mitoq, mitochondrially-targeted coenzyme q, reactive oxygen species, uchl1, ubiquitin carboxyl-terminal hydrolase l1, mitochondrial dysfunction

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