Intracellular Traffic and Neurodegenerative Disorders PDF Download

Author: Peter H. St.George-Hyslop
Publisher: Springer Science & Business Media
ISBN: 3540879412
Category : Medical
Languages : en
Pages : 188

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Book Description
Many adult onset neurodegenerative diseases arise from the accumulation of misfolded peptides. This book examines the role sub-cellular trafficking pathways play in the pathological accumulation of these misfolded proteins and in attempts to clear them.

Author: Nava Segev
Publisher: Springer Science & Business Media
ISBN: 038793877X
Category : Science
Languages : en
Pages : 459

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Book Description
This book covers the past, present and future of the intra-cellular trafficking field, which has made a quantum leap in the last few decades. It details how the field has developed and evolved as well as examines future directions.

Author: Michael S. Wolfe
Publisher: Academic Press
ISBN: 0128113057
Category : Medical
Languages : en
Pages : 561

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Book Description
The Molecular and Cellular Basis of Neurodegenerative Diseases: Underlying Mechanisms presents the pathology, genetics, biochemistry and cell biology of the major human neurodegenerative diseases, including Alzheimer’s, Parkinson’s, frontotemporal dementia, ALS, Huntington’s, and prion diseases. Edited and authored by internationally recognized leaders in the field, the book's chapters explore their pathogenic commonalities and differences, also including discussions of animal models and prospects for therapeutics. Diseases are presented first, with common mechanisms later. Individual chapters discuss each major neurodegenerative disease, integrating this information to offer multiple molecular and cellular mechanisms that diseases may have in common. This book provides readers with a timely update on this rapidly advancing area of investigation, presenting an invaluable resource for researchers in the field. Covers the spectrum of neurodegenerative diseases and their complex genetic, pathological, biochemical and cellular features Focuses on leading hypotheses regarding the biochemical and cellular dysfunctions that cause neurodegeneration Details features, advantages and limitations of animal models, as well as prospects for therapeutic development Authored by internationally recognized leaders in the field Includes illustrations that help clarify and consolidate complex concepts

Author: Kathleen FitzGerald
Publisher:
ISBN:
Category : Endocytosis
Languages : en
Pages : 172

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Book Description
Endocytosis is a process whereby cargo is transported to and from the plasma membrane, and between organelles, in membrane-bound vesicles. The HIV encoded Nef protein is immunosuppressive and substantially contributes to the overall state of immune dysfunction associated with acquired immune deficiency syndrome. The pathological Nef protein has been implicated in modifying the receptor-mediated endocytic pathway. The transmissible spongiform encephalopathies caused by the infectious prion protein from a group of fatal neurodegenerative disorders that affect both animals and human. The trafficking of the prion protein is considered to play an essential role in its pathogenic conversion while the route and mechanism of the pathological prion protein remain controversial. The objective of this work was to investigate the intracellular trafficking of these two pathological proteins, Nef and prion, with emphasis on the localization and effects of Nef on proteins associated with the receptor-mediated endocytic pathway and emphasis on the cellular trafficking of the prion protein. Nef localizes primarily to the early sorting endosome and shows dramatic effects on the redistribution of the recycling compartment-associated proteins, Rab 11 and REM-1. Expression of the Nef mutant E160A, which is disrupted in its' ability to recruit the adaptor protein complex AP-3, resulted in a redistribution of the Rab11-positive compartment while having no effect on the localization of the RME-1 positive tubules. In contrast, expression of the Nef mutant LL164/165AA, which is disrupted in its' ability to recruit AP-1 and AP-3, results in a normal recycling compartment phenotype. These results suggest that Nefs' effect on the receptor-mediated endocytic pathway relies on its' ability to interact with adaptor protein complexes. A proportion of the pathological prion protein localized to the Rab4-positive early sorting endosome and recycling compartment. Analysis of the Rab4-positive compartment revealed that the form of the prion protein present was unglycosylated. Subsequently it was shown that trafficking of the prion protein through the caveolar pathway converged with the receptor-mediated endocytic pathway. The cause and significance of two distint pathways converging, with respect to prion protein trafficking, remains to be determined. This work raises the possibility that conversion may take place in the Rab4-positive compartment as it is consistent with previous data stating that conversion from normal to infectious prion protein takes place in an acidic environment similar to that found in endosomes and that conversion of the prion protein favours the unglycosylated form of the protein.

Author: Susan J. Foss
Publisher:
ISBN:
Category :
Languages : en
Pages :

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Book Description
An axon is a long, thin projection away from a neuron. Axonal transport, a crucial process for the survival of a neuron, is the transport of various organelles and proteins along microtubules, which act as an intracellular highway. Disruptions of axonal transport is associated with many neurodegenerative disorders such as motor neuron diseases (including ALS), Alzheimer's disease, and Huntington's disease. In these diseases, we frequently observe local accumulations of cargoes, which resemble highway traffic jams with pileups of cars. It has been hypothesized that these diseases result from "intracellular traffic jams" caused by the interactions of cargoes. In this thesis, we test this hypothesis using a stochastic model that describes cargoes as interacting particles that switch between different moving and pausing states. Specifically, we apply this model to the transport of neurofilaments. Our results suggest that, although the model can generate traffic jams under certain parameter regimes, these jams may be fundamentally different from those observed in diseases. Another conclusion of this model is that low processivity of the molecular motors that transport neurofilaments help avoid intracellular jams. This explains the evolutionary question, "why is the system is designed this way?".

Author: Leslie L. Iversen
Publisher:
ISBN: 0195373030
Category : Medical
Languages : en
Pages : 632

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Book Description
The discovery of dopamine in 1957-1958 was one of the seminal events in the development of modern neuroscience, and has been extremely important for the development of modern therapies of neurological and psychiatric disorders. Dopamine has a fundamental role in almost all aspects of behavior: from motor control to mood regulation, cognition and addiction and reward, and dopamine research has been unique within the neurosciences in the way it has bridged basic science and clinical practice. Over the decades research into the role of dopamine in health and disease has been in the forefront of modern neuroscience. The Dopamine Handbook is the first single-volume publication to capture current progress and excitement in this dynamic research field.

Author: Eric Anderson
Publisher:
ISBN:
Category :
Languages : en
Pages : 167

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Book Description
The intracellular transport of protein complexes, membrane-bound vesicles, organelles, and RNA along microtubule (MT) tracks to the axonal terminal is crucial for neuronal survival and function. In neurodegenerative disorders, such as Parkinson's disease (PD), defects in the axonal transport pathway are suggested to be major contributors to neurodegeneration. a-syn (a-syn) is a small acid protein that is actively transported from the cell body to the axonal terminal and is the main constituent of Lewy bodies (LB), abnormal deposits of protein in the brain in PD. In my dissertation research, I have focused on the mechanism of a-syn transport in axons. The effects of familial PD (fPD) mutations on the transport of a-syn and synaptic proteins were also studied using Drosophila melanogaster (fruit flies) as a model organism. I have found that the aggregate-prone non-amyloidal component (NAC) region in a-syn was required for the dimerization and membrane binding for a-syn during its transport to the axonal terminal. Deletion of a-syn NAC region (delNAC) resulted in an increase in its accumulation within cell bodies located in the brain, decreased its entry into axons, and its transport to the axonal terminal. This decrease in the transport of delNAC to the axonal terminal is due to decreased membrane interaction of a-syn. I have also demonstrated that increased levels of a-syn (3-fold increase mimicking gene triplication in PD or fPD mutation (Alanine53Threoine, A53T)) accumulation in axons disrupt the axonal transport of synaptic proteins, resulting in synaptic morphological defects and locomotion behavior defects. This accumulation of Îł-syn in axons is likely due to dimerization of Îł-syn through the NAC region, possibly on membranes. Therefore, this part of the study revealed an important role for the NAC region in mediating a-syn dimerization on membranes for a-syn transport to the axonal terminal. The second part of the study focused on the effects of a-syn on Rab3 motility. The Rab3 protein, a neuronal guanosine triphosphate (GTP)-binding protein, has been proposed to present together with a-syn on vesicles and has a similar function in regulating synaptic vesicle trafficking. In vivo live image analysis showed disruption of Rab3 motility with excess or fPD mutant a-syn, and mutant Rab3 disrupted the transport of a-syn-containing vesicle to the axonal terminal. Thus, this study highlights, for the first time, a potential interaction between Rab3 and a-syn in the axonal transport pathway. Collectively, these studies provided new insights into our understanding of the a-syn protein in the axonal transport pathway. Alteration in the axonal transport pathway can have important implications in PD, thus, elucidating the mechanism of a-syn protein transport and Îł-syn-mediated disruption of the axonal transport pathway is critical to our overall understanding of the contribution of this pathway to the disease progression.

Author: Heiko Braak
Publisher: Springer
ISBN: 9783540798491
Category : Medical
Languages : en
Pages : 119

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Book Description
The synucleinopathy sporadic Parkinson’s disease (sPD) is the second most frequent degenerative disorder of the human nervous system after Alzheimer’s disease. The propensity for developing sPD exists in all ethnic groups worldwide, and the prevalence of the disorder increases considerably with age, thereby imposing an enormous social and economic burden on societies with increased life expectancy. The sPD-associated pathological process is progressive, does not go into remission, and can take decades to reach its culmination if it is not be terminated prematurely by death owing to other causes. Against the background of the normal morphology and anatomy, the authors analyze the pathoanatomy of sPD in the nervous system at various neuropathological stages and summarize the potential functional consequences of the lesions.

Author: Robert Vink
Publisher: University of Adelaide Press
ISBN: 0987073052
Category : Medical
Languages : en
Pages : 354

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Book Description
The brain is the most complex organ in our body. Indeed, it is perhaps the most complex structure we have ever encountered in nature. Both structurally and functionally, there are many peculiarities that differentiate the brain from all other organs. The brain is our connection to the world around us and by governing nervous system and higher function, any disturbance induces severe neurological and psychiatric disorders that can have a devastating effect on quality of life. Our understanding of the physiology and biochemistry of the brain has improved dramatically in the last two decades. In particular, the critical role of cations, including magnesium, has become evident, even if incompletely understood at a mechanistic level. The exact role and regulation of magnesium, in particular, remains elusive, largely because intracellular levels are so difficult to routinely quantify. Nonetheless, the importance of magnesium to normal central nervous system activity is self-evident given the complicated homeostatic mechanisms that maintain the concentration of this cation within strict limits essential for normal physiology and metabolism. There is also considerable accumulating evidence to suggest alterations to some brain functions in both normal and pathological conditions may be linked to alterations in local magnesium concentration. This book, containing chapters written by some of the foremost experts in the field of magnesium research, brings together the latest in experimental and clinical magnesium research as it relates to the central nervous system. It offers a complete and updated view of magnesiums involvement in central nervous system function and in so doing, brings together two main pillars of contemporary neuroscience research, namely providing an explanation for the molecular mechanisms involved in brain function, and emphasizing the connections between the molecular changes and behavior. It is the untiring efforts of those magnesium researchers who have dedicated their lives to unraveling the mysteries of magnesiums role in biological systems that has inspired the collation of this volume of work.

Author: Clévio Nóbrega
Publisher: Springer
ISBN: 3319717790
Category : Medical
Languages : en
Pages : 467

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Book Description
This book provides a cutting-edge review of polyglutamine disorders. It primarily focuses on two main aspects: (1) the mechanisms underlying the pathologies’ development and progression, and (2) the therapeutic strategies that are currently being explored to stop or delay disease progression. Polyglutamine (polyQ) disorders are a group of inherited neurodegenerative diseases with a fatal outcome that are caused by an abnormal expansion of a coding trinucleotide repeat (CAG), which is then translated in an abnormal protein with an elongated glutamine tract (Q). To date, nine polyQ disorders have been identified and described: dentatorubral-pallidoluysian atrophy (DRPLA); Huntington’s disease (HD); spinal–bulbar muscular atrophy (SBMA); and six spinocerebellar ataxias (SCA 1, 2, 3, 6, 7, and 17). The genetic basis of polyQ disorders is well established and described, and despite important advances that have opened up the possibility of generating genetic models of the disease, the mechanisms that cause neuronal degeneration are still largely unknown and there is currently no treatment available for these disorders. Further, it is believed that the different polyQ may share some mechanisms and pathways contributing to neurodegeneration and disease progression.