Stress Activated Protein Kinases And Neurodegenerative Disease

In this book leading researchers in the field discuss the state-of-the-art of many aspects of SAPK signaling in various systems from yeast to mammals. These include various chapters on regulatory mechanisms as well as the contribution of the SAPK signaling pathways to processes such as gene expression, metabolism, cell cycle regulation, immune responses and tumorigenesis. Written by international experts, the book will appeal to cell biologists and biochemists.

This book brings together some of the best researchers in the field of aging and neurodegenerative diseases and presents up-to-date information concerning new developments in this exciting area of research in quite separate fields of biomedical science. It includes a wide range of issues such as basic and applied concepts, methods, and techniques used in this area. The chapters examine and evaluate our understanding of the pathogenetic mechanisms involved in these fields such as increased protein oxidation and macromolecular modifications associated with aging. This is a novel strategy for the visualization of ROS-induced protein oxidation and protection by antioxidants in living cells using fluorescent probes, thermochemiluminescence (TCL) methodology for determination of the oxidative status of biological systems in experimental and clinical setups, protein degradation, proteasome inactivation observed in the aging process or caused by oxidative stress.Other topics addressed are the oxidative stress theory of aging, oxidation and removal of protein aggregates in neurodegeneration, causes and consequences of oxidative stress in Alzheimer's disease, assessment of antioxidants as a therapeutic for neurodegenerative diseases, rafts and prions, the many forms of the prion protein and its subcellular pathways, signaling pathways in protection of neural tissues by ischemic and drug-induced preconditioning, folding of proteins associated with neurodegenerative disorders and aging and neuroprotection in immuno-mediated neurodegeneration from infection to autoimmunity.

Oxidative Stress and Age-Related Neurodegeneration brings together researchers from a variety of fields to compare normal aging and disease-related neurodegeneration in terms of susceptibility to and effects of oxidative stress. They address how these effects can be attenuated, and examine whether antioxidants and natural micronutrients, such as those found in Gingko biloba, green tea, blueberries, and grape seed extract, can play a role. The book includes various ways research is getting to the core of neurodegenerative disease, including the use of proteomics, comparisons to related diseases, and examinations at the cellular and molecular levels.

Protein phosphorylation via protein kinases is an inevitable process that alters physiological and pathological functions of the cells. Thus, protein kinases play key roles in the regulation of cell life or death decisions. Protein kinases are frequently a driving factor in a variety of human diseases including aging and cellular senescence, immune system and endothelial dysfunctions, cancers, insulin resistance, cholestasis and neurodegenerative diseases, as well as bacterial resistance in persistent infections. Recent developments in quantitative proteomics provide important opinions on kinase inhibitor selectivity and their modes of action in the biological context. Protein Kinase-mediated Decisions Between Life and Death aims to have the reader catch insights about up-to-date opinions on “Protein Kinases” related pathways that threaten human health and life. As “Protein Kinases” are related to many health problems, clinicians, basic science researchers and students need this information. Chapter “Signal Transduction in Immune Cells and Protein Kinases” is available open access under a Creative Commons Attribution 4.0 International License via link.springer.com.

Loss of post-mitotic neurons from the adult brain underlies the pathology of neurodegenerative diseases and neurotoxin exposure. Neuronal cell death occurs by two mechanisms; necrosis and apoptosis. Apoptosis is a process whereby developmental cues and environmental stimuli activate a genetic program to implement a series of steps that culminate in cell death. An important aspect of apoptosis is that it can be halted and such interventions may rescue dying neurons. The overall goal of this project is to identify key protein kinases involved in regulating neuronal survival and apoptosis. The aims for the first year of funding, as described in the Statement of Work, were to: (1) Define key protein kinase cascades regulated by neutrophic factors in neurons, and (2) Modulate the protein kinase cascades regulated by neurotrophic factors and determine the consequence on neuronal survival and death. In the last year, we have identified 3 different protein kinases that regulate neuronal survival and a few of the downstream targets of these kinases. We have also shown that treatment of brain grafts with neurotrophic factors or inhibitors of stress-activated protein kinases increase survival of transplanted dopaminergic neurons in hemi-parkinsonian rats. These studies have resulted in 6 published manuscripts and 4 abstracts presented at national scientific meetings.

With the prevalence of neurodegenerative diseases on the rise as average life expectancy increases, the hunt for effective treatments and preventive measures for these disorders is a pressing challenge. Neurodegenerative disorders such as Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and amyotrophic lateral sclerosis have been termed ‘protein misfolding disorders’ that are char- terized by the neural accumulation of protein aggregates. Manipulation of the cellular stress response involving the induction of heat shock proteins offers a the- peutic strategy to counter conformational changes in neural proteins that trigger pathogenic cascades resulting in neurodegenerative diseases. Heat shock proteins are protein repair agents that provide a line of defense against misfolded, aggregati- prone proteins. Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection reviews current progress on neural heat shock proteins (HSP) in relation to neurodegenerative diseases (Part I), neuroprotection (Part II), ext- cellular HSP (Part III) and aging and control of life span (Part IV). Key basic and clinical research laboratories from major universities and hospitals around the world contribute chapters that review present research activity and importantly project the field into the future. The book is a must read for researchers, postdoctoral fellows and graduate students in the fields of Neuroscience, Neurodegenerative Diseases, Molecular Medicine, Aging, Physiology, Pharmacology and Pathology.

The health of the proteome depends upon protein quality control to regulate the proper synthesis, folding, translocation, and clearance of proteins. The cell is challenged constantly by environmental and physiological stress, aging, and the chronic expressions of disease associated misfolded proteins. Substantial evidence supports the hypothesis that the expression of damaged proteins initiates a cascade of molecular events that leads to Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, and other diseases of protein conformation.

Soldiers deployed to high altitude terrain or exposed to chemical toxins that induce ischemia or impaired oxidative metabolism in the central nervous system (CNS) encounter sustained cellular hypoxia. This can compromise CNS function and lead to permanent neuronal injury, which is a precursor for neurodegenerative disorders such as Alzheimer's disease. The proposed research is designed to determine the role of stress-activated signal transduction systems in regulating a cellular phenotype that is tolerant to hypoxic stress. We hypothesize that de novo gene expression is a major component of the adaptative/protective response to hypoxia, and that the p38 kinase stress-activated pathway plays a major role in this response. We present novel preliminary findings, which show that genes involved in cell proliferation and differentiation are regulated by hypoxia and p38. We hypothesize that these genes and the genes that encode immediate early transcription factors, and the hypoxia-sensitive potassium channels are regulated by p38 during hypoxia and play a major role in protecting neurons form hypoxia injury and neurodegenerative disease. Studies are performed in PC 12 cells, which are extremely tolerant to reduced oxygen and a widely used model for elucidating the molecular mechanisms of neural function. The objectives of the proposed research are: 1) Identify the p38 isoforms that are activated by hypoxia. Determine the effects of hypoxia on the protein kinases and small 0-proteins that lie upstream of p38. 2) Determine the role of the p38 kinase pathway on the unique hypoxia-induced regulation of cyclin A, and immediate early genes in the fos and jun families. 3) Determine the role of the p38 kinase pathway in regulating the hypoxia-induced expression of the oxygen-sensitive Kv1 .2 potassium channel.

The primary objective of this research project is to determine the role of the mitogen-activated protein kinase (MAPK) pathways (specifically p38 kinase) in mediating the cellular response to hypoxia-stress. The overall scope of this project is to understand how neurons adapt to chronic hypoxia. The neural-like PCl2 cell line is used as a model system to identify the molecular mechanisms that mediate tolerance to hypoxia. The inability to develop tolerance can lead to neurodegeneration and possibly cell death. Our work on this project resulted in the publication of 4 original papers, 1 review paper, and 1 book chapter. We found that exposure to prolonged hypoxia activates the p38 alpha and p38 gamma isoforms, but not the p38 beta% or p38 delta isoforms of the p38 kinase pathway. We showed that the down-stream targets of these p38 kinase isoforms are cyclin Dl and a cyclin A-like molecule. We propose that activation of these cyclins during hypoxia stimulates cell proliferation and might protect neurons in the intact nervous system against damaging effects of hypoxia. We also discovered that the activation of the hypoxia-induced transcription factor, EPAS1, is regulated by the p42/p44 MAPK pathway, but in a manner that is independent of ras but dependent on calcium/calmodulin.