1. Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease
- Author
-
Samantha Giordano, Jianhua Zhang, and Victor M. Darley-Usmar
- Subjects
Aging ,Antioxidant ,Redox signaling ,MPP+, 1-methyl-4-phenylpyridinium ,medicine.medical_treatment ,PINK1, PTEN-induced putative kinase 1 ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,HNE, 4-hydroxynonenal ,Protein oxidation ,medicine.disease_cause ,Biochemistry ,Antioxidants ,Lipid peroxidation ,Antiparkinson Agents ,chemistry.chemical_compound ,rasagiline, N-propargyl-1-(R)-aminoindan ,Clinical trials ,GSH, glutathione ,Toxins ,TFEB, transcription factor EB ,lcsh:QH301-705.5 ,MitoQ, mitochondrially-targeted coenzyme Q ,Neurons ,Clinical Trials as Topic ,MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine ,lcsh:R5-920 ,6-OHDA, 6-hydroxydopamine ,ROS/RNS, reactive oxygen and nitrogen species ,Neurodegeneration ,Brain ,Neurodegenerative Diseases ,curcumin, (1E,6E)-1,7-Bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione ,LRRK2, leucine-rich repeat kinase 2 ,Animal models ,Sirt1, NAD-dependent deacetylast sirtuin-1 ,Neuroprotective Agents ,the ADAGIO study, the Attenuation of Disease Progression with Azilect Given Once-daily) study ,Protein aggregation ,Oxidoreductases ,lcsh:Medicine (General) ,Oxidation-Reduction ,DNA damage ,CBZ, carbamazepine ,Nerve Tissue Proteins ,Biology ,Nrf2, Nuclear factor (erythroid-derived 2)-like 2 ,Article ,iPSC, induced pluripotent stem cells ,Parkinsonian Disorders ,Peroxynitrous Acid ,SOD, superoxide dismutase ,medicine ,Autophagy ,Animals ,Humans ,MnSOD, manganese superoxide dismutase ,UPDRS, Unified Parkinson’s Disease Rating Scale ,MDA, malondialdehyde ,MitoQ ,Organic Chemistry ,the DATATOP Study, the Deprenyl and Tocopherol Antioxidative Therapy of Parkinsonism Study ,Selegiline, N-propargyl-methamphetamine ,medicine.disease ,UCHL1, ubiquitin carboxyl-terminal hydrolase L1 ,Disease Models, Animal ,Oxidative Stress ,chemistry ,lcsh:Biology (General) ,the TEMPO Study, the TVP-1012 in Early Monotherapy for PD Outpatients Study ,Parkinson’s disease ,Anti-oxidants ,Lipid Peroxidation ,the NET-PD network, the NINDS Exploratory Trials in Parkinson’s Disease (NET-PD) network ,Lysosomes ,Mitochondrial dysfunction ,Reactive oxygen species ,EGCG, epigallocatechin gallate ,Oxidative stress ,HIF1α, hypoxia-inducible factor 1-alpha - 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.
- Published
- 2014