Accepted Manuscript Title: OXIDATIVE STRESS and NEURODEGENERATION Author: Jianhua Zhang PII: DOI: Reference:
S0361-9230(17)30249-6 http://dx.doi.org/doi:10.1016/j.brainresbull.2017.04.018 BRB 9212
To appear in:
Brain Research Bulletin
Author: D. Allan Butterfield PII: DOI: Reference:
S0361-9230(17)30249-6 http://dx.doi.org/doi:10.1016/j.brainresbull.2017.04.018 BRB 9212
To appear in:
Brain Research Bulletin
Please cite this article as: D.Allan Butterfield, STRESS and NEURODEGENERATION, Brain Bulletinhttp://dx.doi.org/10.1016/j.brainresbull.2017.04.018
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OXIDATIVE STRESS and NEURODEGENERATION
Jianhua Zhang1,* and D. Allan Butterfield2,*
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294 Department of Chemistry and Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40506
Correspondence may be addressed to either author:
Jianhua Zhang, Ph.D, Department of Pathology, University of Alabama at Birmingham Birmingham, AL 35394 ,Email: [email protected]
OR D. Allan Butterfield, Ph.D., Department of Chemistry and Sanders-Brown Center on Aging University of Kentucky, Lexington, KY 40506 ,Email: [email protected]
Strong evidence supports the involvement of oxidative stress in neurodegeneration . Mitochondrial metabolism is required for the activity of neurons and oxygen consumption in these post-mitotic cells invariably leads to generation of reactive oxygen species that can modify lipids, DNA and proteins. Neuroinflammation occurs in response to displaced or aberrantly shaped proteins and nucleic acids . Environmental exposures
of chemicals may also promote generation of oxidants that also play a role in pathogenesis of neurodegenerative diseases . What can we learn from these studies? This Special Issue is comprised of current reviews and research articles related to the field. In particular in Parkinson disease, alpha-synuclein misfolding and aggregation occurs. What is the role of metabolism, mitochondrial quality control, and neuroinflammation in alpha-synucleinopathy? What is the role of protein post-translational modification in response to changes in glucose metabolism in signaling neuroprotective or neurodegenerative events? Anandhan et al. review the link between metabolic dysfunction, energy failure and redox homeostasis . Special attention is paid to astrocyte-neuron interaction in energy sources and redox homeostasis. It has been hypothesized that astrocytes preferentially consume glucose and shuttle lactate to neurons as an energy source. Not surprisingly, different regions of the brain use glycolysis to different extents. Interestingly, an increase in oxygen and glucose supply in response to an increase in blood flow increases glycolysis but not oxygen consumption. In Parkinson disease, the lower number of astrocytes and higher number of microglia in substantia nigra may contribute to lack of neurotrophic, energetic and antioxidant support, and increased exposure to pro-inflammatory cytokines. The authors provide a comprehensive review regarding various aspects of mitochondrial dysfunction, caused by familial gene mutations or environmental toxins, and consequent defective mitochondrial transport, biogenesis and dynamics, and quality control. The cellular and subcellular sources of reactive oxygen species and antioxidants also are summarized. Finally, how glucose metabolism is controlled in neurons and affected in Parkinson disease is discussed. As metabolic and redox programming is the foundation for cellular function and survival, information from this review may inspire further studies focusing on the regulation of redox homeostasis and nutrient utilization/energetic pathways with regard to neurodegeneration research. Barodia et al. discuss the role of mitochondria in quality control and focus on the role of Parkin and PINK1 function, as both proteins have been associated in Parkinson’s disease . Their review summarizes several aspects of Parkin and PINK1 biology, including: their domain structures and functions in model systems, the common and independent functions of both proteins, their involvement in mitophagy and neuroinflammation, how their loss of function affects phenotypes in humans and in Parkinson’s disease animal models, and the therapeutic implications of their involvement in neurodegeneration. This review provides insights into upstream
regulatory mechanisms of Parkin and PINK1 function and downstream targets of their function, both of which conceivably can be further tapped into as potential therapeutic targets. Rokad et al. focus on alpha-synuclein protein misfolding and aggregation . These latter authors provide a comprehensive review of epidemiological and experimental evidence on the association of alpha-synuclein accumulation in the brain with oxidative stress in response to metal, pesticide, and traumatic brain injury. Importantly, post-translational modification of alpha-synuclein, its translocation to the mitochondria and its degradation by the proteasomes also are highlighted. Wani et al. present evidence that not all post-translational modifications are bad for neurons . OGlcNAcylation is a nutrient and stress sensing protein modification, integrating glucose metabolism to cell signaling. O-GlcNAcylation on Ser/Thr residues can occur at sites amendable for phosphorylation as well as sites that are not generally phosphorylated. Despite of the crucial role of O-GlcNAcylation on cell signaling and neurodegeneration, investigation of selective protein O-GlcNAcylation is not as advanced as the studies on phosphorylation. One would anticipate that development of site-specific antibodies against O-GlcNAcylated specific peptides may vastly advance the field as has been the case in studying phosphorylation. Alzheimer disease (AD) has been associated with, and may be related to, oxidative stress .. Dementia has many causes, but by far the largest contributor to the population of people with clinical dementia is AD. Given the immense challenges this disease currently provides to public health and what is predicted to cost up to $2 trillion annually by 2050, in addition to the enormous human cost, better understanding of the molecular basis of AD is essential for a disease-modifying. Redox proteomics, which leads to the identification of oxidatively modified and most often dysfunctional brain proteins , coupled with oxidative stress associated with amyloid beta-peptide (A42) oligomers, is reviewed with respect to AD by Butterfield and colleagues in this special issue . Strong evidence supporting the notion that oxidatively posttranslationally modified enzymes involved in glucose metabolism trigger neurodegeneration throughout the progress of AD is presented. Consistent with this above review article, the review by Wilkins and Swerdlow describes in depth amyloid precursor protein (APP) molecular processing from which A oligomers arise . These authors specifically review data that addresses how mitochondrial function and biogenergetics modify APP processing and A production.
Vascular dementia is the second most common form of dementia after AD. In an original research paper, Prakash and coworkers report studies of a rodent model of vascular dementia . Oxidative stress, biochemical and behavioral parameters were determined to be highly damaged. Administration of a dual endothelin receptor antagonist, bosentan, significantly modulated these damaging effects of this model of vascular dementia. In a number of neurodegenerative disorders, including in early stages of AD  and in traumatic brain injury , biomolecule nitration, indexed primarily by elevated levels of 3-nitrotyrosine and other indices, is evident. In an elegant paper by Estevez and colleagues, the authors describe the mechanisms by which protein, lipid, and DNA nitration occurs via peroxynitrite and how this posttranslational modification leads to neurodegeneration . The authors review studies of the role of peroxynitrite in necrosis, apoptosis, autophagy, parthanatos, and necroptosis, processes that are dependent on the level and length of exposure to peroxynitrite, the latter formed by radical-radical combination of nitric oxide and superoxide anion . Li and coworkers report results on early brain injury (EBI) following subarachnoid hemorrhage (SAH) in rodents that leads to significant brain damage assessed by degree of SAH, brain edema, blood-brain permeability, changes in oxidative stress factors, apoptosis markers, and altered signaling pathways (14). Administration of naringin, a major flavonone glycoside found in grapefruits and citrus fruits, significantly ameliorated these damaging effects of EBI following SAH. In conclusion, reviews and research articles in this special issue of Brain Research Bulletin on Oxidative Stress and Neurodegeneration pay special attention to the involvement of metabolic and redox aspects of neurodegeneration (Fig.1). The neurodegenerative environment, including nutrient availability, energy production mechanisms, reactive species, inter-cellular communication, play important roles in disease pathogenesis. Understanding how this environment is regulated, including redox regulation, will bring new insights into development and progression of neurodegeneration and lead to potentially novel and effective strategies for intervention.
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Figure 1. This special issue of Brain Research Bulletin on Oxidative Stress and Neurodegeneration covers the interplay of metabolism, mitochondrial quality control and protein modification on pathogenesis of neurodegeneration. The idea of glia-neuron interaction, both in terms of production of reactive species and in terms of provision of precursors for antioxidants and energy sources, is extensively highlighted. Mechanisms that regulate mitophagy, apoptosis and Parthanatos are described. Furthermore, observations regarding posttranslational modification of proteins as signaling and as glycolytic inhibition mechanisms are reviewed. With the new technical and conceptual development in these areas, opportunities continue to emerge that will enable further investigation of neurodegeneration as a complex redox homeostasis and metabolic disorder, integrating cell signaling, bioenergetics and metabolism that may significantly impact the field in years to come.