[PDF] Toxicity And Autophagy In Neurodegenerative Disorders eBook
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Comprehensive overview of different aspects of autophagy as it relates to neurodegenerative diseases. The pathogenesis of the main neurodegenerative disorders includes either the accumulation of altered or misfolded proteins or exposure to several toxics. Autophagy constitute one of the two principal cellular pathways implicate in the clearance of these material and can serve as a neuroprotective mechanism. Topics include: the role of autophagy in the brain, the role of autophagy in the principal neurodegenerative disorders, and the mechanism by which different molecules cause neurotoxicity and the role autophagy plays.
To date, three forms of autophagy – macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) – have been identified. Recently, we discovered a novel type of autophagy, “RNautophagy,” in which RNA is taken up directly into lysosomes for degradation. Gain of toxic functions of accumulated misfolded proteins or abnormal RNAs in CNS participate to a considerable degree in the pathogenesis of various neurodegenerative diseases. Thus, degradation and clearance of the toxic species by autophagy systems may be important for the maintenance of neurons and prevention of neurodegenerative diseases. We showed that amyotrophic lateral sclerosis (ALS)-linked mutant SOD1 is degraded not only by the proteasome but also by macroautophagy, and that macroautophagy reduces mutant SOD1-mediated toxicity. We found that Parkinson’s disease-associated mutant UCH-L1 interacts with LAMP-2A and Hsc70, which are the components of CMA machinery, and inhibits CMA. Because RNAs containing aberrant repeats are thought to cause some of ALS or spinocerebellar ataxia (SCA), RNautophagy may also play significant roles in the pathology of neurodegenerative diseases.
Autophagy is a highly regulated process that promotes vital cellular homeostasis by allowing bulk non-specific degradation of the cytoplasmic contents, mainly damaged and/or surplus organelles and proteins. Autophagy is ubiquitous in eukaryotes, highly conserved from yeast to mammals, and occurs in all mammalian tissues. Historically, autophagy was characterized as the coping response to limited energy resources (starvation), to generate additional biomolecular raw materials. However, research in the past two decades has demonstrated the indispensible roles of autophagy in eukaryotic physiology and pathology with respect to wide-ranging processes such as development, differentiation, aging, immunity, cancer biology, and neurodegenerative disorders. In this chapter, we will provide an overview of the types of autophagy and mechanisms of the autophagy pathway followed by a discussion of the current understanding of the role of autophagy in neuronal physiology, pathology of neurodegenerative disorders, and potential therapeutic approaches.
What is autophagy? Why would neurons digest parts of themselves through autophagy? How can autophagy save the lives of cells under some conditions, but act as an accomplice to cell death in others? By what mechanisms are autophagy-related processes dysregulated in neurological diseases, and are there therapeutic strategies to correct or compensate for their dysfunction? This book provides an expert view of major concepts in autophagy research with a focus on autophagy in neurons. Experimental evidence for evolutionarily conserved and specialized regulatory mechanisms for autophagy in the mammalian nervous system will be presented, including recent data on braking mechanisms. Areas of intersection with cell death, the ubiquitin-proteasome system, chaperone-mediated autophagy, and the endocytic pathway will be reviewed, along with emerging areas of mitochondrial autophagy (mitophagy) and the autophagic regulation of neuritic/synaptic processes. Advances in delineating mechanisms by which autophagy is involved in the pathophysiology of neurological disorders, including Alzheimer's, Parkinson's, Huntington's, amyotrophic lateral sclerosis, ischemia/hypoxia and lysosomal storage diseases, will be discussed along with current drug development strategies targeting autophagy.
Oxidative stress is the result of an imbalance in pro-oxidant/antioxidant homeostasis that leads to the generation of toxic reactive oxygen species. Brain cells are continuously exposed to reactive oxygen species generated by oxidative metabolism, and in certain pathological conditions defense mechanisms against oxygen radicals may be weakened and/or overwhelmed. DNA is a potential target for oxidative damage, and genomic damage can contribute to neuropathogenesis. It is important therefore to identify tools for the quantitative analysis of DNA damage in models on neurological disorders. This book presents detailed information on various neurodegenerative disorders and their connection with oxidative stress. This information will provide clinicians with directions to treat these disorders with appropriate therapy and is also of vital importance for the drug industries for the design of new drugs for treatment of degenerative disorders. * Contains the latest information on the subject of neurodegenerative disorders* Reflects on various factors involved in degeneration and gives suggestions for how to tackle these problems
Autophagy in Health and Disease, Volume 175, presents the latest insights from renowned experts in the field who discuss the key role of autophagic responses in the preservation of cellular and organismal homeostasis and how defects in the molecular apparatus for autophagy drive or accompany disease. Specific chapters in this new release include Crosstalk between autophagy and cell death signaling: mechanisms and therapeutic relevance, C. elegans to model autophagy-related human disorders, Autophagy in Kidney Disease: advances and therapeutic potential, Autophagy in Chronic Lung Disease, Autophagy in motoneuronal disorders, Strategies employed by viruses to manipulate autophagy, and much more. Provides an outstanding panel of recognized experts in the field who discuss the latest in autophagy Includes critical discussions of autophagy in the context of each major human disorder Models autophagy-related human pathologies in lower eukaryotes
Neurodegenerative disorders are characterized by the progressive loss of specific populations of neurons with consequent deterioration of brain's function and dramatic impact on human behavior. At present, there are no effective cures for neurodegenerative diseases. Because unambiguous diagnosis is possible only after manifestation of symptoms, when a large proportion of neurons has been already lost, therapies are necessarily confined to alleviation of symptoms. Development of cures halting the disease course is hampered by our rudimentary understanding of the etiopathology. Most neurodegenerative disorders are sporadic and age-related and - even for those of known genetic origin - the mechanisms influencing disease onset and progression have not been fully characterized. The different diseases, however, share important similarities in the mechanisms responsible for neuronal loss, which is caused by a combination of endogenous and exogenous challenges. Trophic deprivation, oxidative stress, accumulation of abnormal protein aggregates, and bioenergetics defects have been described in most, if not all, neurodegenerative disease. To counterbalance these noxious stimuli cells deploy, at least during the initial pathogenic states, intrinsic neuroprotective responses. These are general compensatory mechanisms, common to several neurodegenerative conditions, which reprogram cellular physiology to overcome stress. Adaptation includes strategies to optimize energetic resources, for instance reduction of rRNA synthesis to repress translation, suppression of transcription, and bioenergetics and metabolic redesign. Additional mechanisms include potentiation of antioxidant capacity, induction of endoplasmic reticulum (ER) stress, and activation of protein quality control systems and autophagy. Ineffective execution of these compensatory strategies severely threatens cellular homeostasis and favors onset of pathology. Therefore, a better understanding of these "buffering" mechanisms and of their interconnections may help to devise more effective therapeutic tools to prolong neuronal survival and activity, independently of the original genetic mutations and stress insults. This Research Topic focuses on the initial compensatory responses protecting against failure of those mechanisms that sustain neuronal survival and activity. The collection intends to summarize the state-of-the-art in this field and to propose novel research contributes, with the ultimate goal of inspiring innovative studies aimed to contrast progression of neurodegenerative diseases.
Autophagy Dysfunction in Alzheimer’s Disease and Dementia provides an overview for researchers and clinicians on the mechanisms involved in protein degradation in Alzheimer’s. The book discusses the implication of autophagy dysfunction in these diseases and how it causes degenerated proteins, including aggregated tau and aggregated amyloid protein. Other sections explores the possibilities of potential drug development through autophagy modulation, making this a great resource on the study of how autophagy dysfunction has been linked to the accumulation of misfolded proteins that cause death of neurons in Alzheimer’s and other neurodegenerative diseases. Discusses the implication of autophagy dysfunction in neurodegenerative diseases Highlights the mechanisms involved in protein degradation Explores the possibilities of drug development through autophagy modulation