Understanding the Role of Stress Granules (SGs) in the Pathophysiology of Principle Neurodegenerative Diseases: ALS, AD & FTD (Frontotemporal Dementia). PDF Download
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Author: Dr. Hakim Saboowala
Publisher: Dr.Hakim Saboowala
ISBN:
Category : Medical
Languages : en
Pages : 80
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Book Description
For years, the pathological processes contributing to the accumulation of aggregates in neurological diseases were thought to result mainly from non-physiological aggregation of proteins prone to misfolding, which then accumulated because of progressive, age-related deficits in the proteostatic systems, including the proteasomal and autophagic systems. Recent advances suggest that the response that RNA metabolism plays in stress has an important role in the pathophysiology of neurodegenerative diseases, particularly: · Amyotrophic lateral sclerosis, · Frontotemporal dementias and · Alzheimer disease. RNA-binding proteins (RBPs) control the utilization of mRNA during stress, in part through the formation of membrane-less organelles termed stress granules (SGs). These structures form through a process of liquid–liquid phase separation. Major signaling pathways regulating SG formation include the mammalian target of rapamycin (mTOR)–eukaryotic translation initiation factor 4F (eIF4F) and eIF2α pathways, whereas pathways regulating SG dispersion and removal are mediated by valosin-containing protein and the autolysosomal cascade. Post-translational modifications of RBPs also strongly contribute to the regulation of SGs. Evidence indicates that SGs are supposed to be transient structures, but the chronic stresses associated with ageing lead to chronic persistent SGs that appear to act as a nidus for the aggregation of disease-related proteins. Thus a model is suggested describing how intrinsic vulnerabilities within cellular RNA metabolism might lead to the pathological aggregation of RBPs when SGs become persistent. This process might accelerate the pathophysiology of many neurodegenerative diseases and myopathies, and suggests new targets for disease intervention. An attempt has been made as usual in this Booklet to cover the biology of SGs and related translational stress responses and presents a model for how dysfunction of these pathways contributes to many neurodegenerative diseases. It is also attempted to review the emerging biology of LLPS and membrane-less organelles and show how the fundamental biology of these processes renders RBPs (and other nucleotide-binding proteins) prone to aggregation and subsequent neurodegenerative responses. …Dr. H. K. Saboowala. M.B.(Bom) .M.R.S.H.(London)
Author: Dr. Hakim Saboowala
Publisher: Dr.Hakim Saboowala
ISBN:
Category : Medical
Languages : en
Pages : 80
Get Book Here
Book Description
For years, the pathological processes contributing to the accumulation of aggregates in neurological diseases were thought to result mainly from non-physiological aggregation of proteins prone to misfolding, which then accumulated because of progressive, age-related deficits in the proteostatic systems, including the proteasomal and autophagic systems. Recent advances suggest that the response that RNA metabolism plays in stress has an important role in the pathophysiology of neurodegenerative diseases, particularly: · Amyotrophic lateral sclerosis, · Frontotemporal dementias and · Alzheimer disease. RNA-binding proteins (RBPs) control the utilization of mRNA during stress, in part through the formation of membrane-less organelles termed stress granules (SGs). These structures form through a process of liquid–liquid phase separation. Major signaling pathways regulating SG formation include the mammalian target of rapamycin (mTOR)–eukaryotic translation initiation factor 4F (eIF4F) and eIF2α pathways, whereas pathways regulating SG dispersion and removal are mediated by valosin-containing protein and the autolysosomal cascade. Post-translational modifications of RBPs also strongly contribute to the regulation of SGs. Evidence indicates that SGs are supposed to be transient structures, but the chronic stresses associated with ageing lead to chronic persistent SGs that appear to act as a nidus for the aggregation of disease-related proteins. Thus a model is suggested describing how intrinsic vulnerabilities within cellular RNA metabolism might lead to the pathological aggregation of RBPs when SGs become persistent. This process might accelerate the pathophysiology of many neurodegenerative diseases and myopathies, and suggests new targets for disease intervention. An attempt has been made as usual in this Booklet to cover the biology of SGs and related translational stress responses and presents a model for how dysfunction of these pathways contributes to many neurodegenerative diseases. It is also attempted to review the emerging biology of LLPS and membrane-less organelles and show how the fundamental biology of these processes renders RBPs (and other nucleotide-binding proteins) prone to aggregation and subsequent neurodegenerative responses. …Dr. H. K. Saboowala. M.B.(Bom) .M.R.S.H.(London)
Author: Mark Yang Fang
Publisher:
ISBN:
Category :
Languages : en
Pages : 163
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Book Description
Stress granules (SG) form during cellular stress and have been linked to neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). Strategies to modulate SGs have the potential to yield insights into their role in pathophysiology. We performed a high-content screen to identify small molecules that alter SG properties in proliferative cells and iPSC-derived motor neurons (iPS-MNs). One major class of hit compounds are nucleic acid intercalating molecules that disrupt recruitment of ALS-associated RNA-binding proteins (RBPs), such as TDP-43 and FUS/TLS, into SGs and reduce accumulation of cytoplasmic TDP-43 in iPS-MNs from ALS patients. These findings corroborate our biochemical results indicating that SGs accumulate ALS-associated RBPs in their shells in an RNA-dependent manner. Thus, SGs contribute to persistent accumulation of TDP-43, and nucleic acid intercalating compounds represent a promising new therapeutic approach for treating ALS/FTD.
Author: Akihiko Takashima
Publisher: Springer Nature
ISBN: 9813293586
Category : Medical
Languages : en
Pages : 416
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Book Description
This book presents essential studies and cutting-edge research results on tau, which is attracting increasing interest as a target for the treatment of Alzheimer's disease. Tau is well known as a microtubule-associated protein that is predominantly localized in the axons of neurons. In various forms of brain disease, neuronal loss occurs, with deposition of hyperphosphorylated tau in the remaining neurons. Important questions remain regarding the way in which tau forms hyperphosphorylated and fibrillar deposits in neurons, and whether tau aggregation represents the toxic pathway leading to neuronal death. With the help of new technologies, researchers are now solving these long-standing questions. In this book, readers will find the latest expert knowledge on all aspects of tau biology, including the structure and role of the tau molecule, tau localization and function, the pathology, drivers, and markers of tauopathies, tau aggregation, and treatments targeting tau. Tau Biology will be an invaluable source of information and fresh ideas for those involved in the development of more effective therapies and for all who seek a better understanding of the biology of the aging brain.
Author: Gabor G. Kovacs
Publisher: Cambridge University Press
ISBN: 1316337650
Category : Medical
Languages : en
Pages : 320
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Book Description
This practical guide to the diagnosis of neurodegenerative diseases discusses modern molecular techniques, morphological classification, fundamentals of clinical symptomology, diagnostic pitfalls and immunostaining protocols. It is based on the proteinopathy concept of neurodegenerative disease, which has influenced classification and provides new strategies for therapy. Numerous high-quality images, including histopathology photomicrographs and neuroradiology scans, accompany the description of morphologic alterations and interpretation of immunoreactivities. Diagnostic methods and criteria are placed within recent developments in neuropathology, including the now widespread application of immunohistochemistry. To aid daily practice, the guide includes diagnostic algorithms and offers personal insights from experienced experts in the field. Special focus is given to the way brain tissue should be handled during diagnosis. This is a must-have reference for medical specialists and specialist medical trainees in the fields of pathology, neuropathology and neurology working with neuropathologic features of neurodegenerative diseases.
Author: Rita Sattler
Publisher: Springer
ISBN: 331989689X
Category : Medical
Languages : en
Pages : 310
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Book Description
It has become evident over the last years that abnormalities in RNA processing play a fundamental part in the pathogenesis of neurodegenerative diseases. Cellular viability depends on proper regulation of RNA metabolism and subsequent protein synthesis, which requires the interplay of many processes including transcription, pre--‐mRNA splicing, mRNA editing as well as mRNA stability, transport and translation. Dysfunction in any of these processes, often caused by mutations in the coding and non--‐ coding RNAs, can be very destructive to the cellular environment and consequently impair neural viability. The result of this RNA toxicity can lead to a toxic gain of function or a loss of function, depending on the nature of the mutation. For example, in repeat expansion disorders, such as the newly discovered hexanucleotide repeat expansion in theC9orf72 gene found in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), a toxic gain of function leads to the formation of RNA foci and the sequestration of RNA binding proteins (RBPs). This in return leads to a loss of function of those RBPs, which is hypothesized to play a significant part in the disease progression of ALS and FTD. Other toxicities arising from repeat expansions are the formation of RNA foci, bi--‐directional transcription and production of repeat associated non--‐ATG (RAN) translation products. This book will touch upon most of these disease mechanisms triggered by aberrant RNA metabolism and will therefore provide a broad perspective of the role of RNA processing and its dysfunction in a variety of neurodegenerative disorders, including ALS, FTD, Alzheimer’s disease, Huntington’s disease, spinal muscular atrophy, myotonic dystrophy and ataxias. The proposed authors are leading scientists in the field and are expected to not only discuss their own work, but to be inclusive of historic as well as late breaking discoveries. The compiled chapters will therefore provide a unique collection of novel studies and hypotheses aimed to describe the consequences of altered RNA processing events and its newest molecular players and pathways.
Author: Marlene Oeffinger
Publisher: Springer Nature
ISBN: 3030314340
Category : Science
Languages : en
Pages : 318
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Book Description
The book provides an overview on the different aspects of gene regulation from an mRNA centric viewpoint, including how mRNA is assembled and self-assembles in a complex consisting of RNA and proteins, and how its ability to be translated at the right time and space depends on many processes acting on the mRNAs, leading to a properly folded complex. This book shows how new technologies have led to a better understanding of these processes and their connected diseases.The book is written for scientists in fundamental and applied biomedical research working on different aspects of gene regulation. It is also targeted to an audience that is not implicated in these fields directly, but wants to gain a better understanding of mRNA biology.
Author: Hardy J. Rideout
Publisher: Springer
ISBN: 3319499696
Category : Medical
Languages : en
Pages : 280
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Book Description
This is the first book to assemble the leading researchers in the field of LRRK2 biology and neurology and provide a snapshot of the current state of knowledge, encompassing all major aspects of its function and dysfunction. The contributors are experts in cell biology and physiology, neurobiology, and medicinal chemistry, bringing a multidisciplinary perspective on the gene and its role in disease. The book covers the identification of LRRK2 as a major contributor to the pathogenesis of Parkinson's Disease. It also discusses the current state of the field after a decade of research, putative normal physiological roles of LRRK2, and the various pathways that have been identified in the search for the mechanism(s) of its induction of neurodegeneration.
Author: Mohammad R. K. Mofrad
Publisher: Cambridge University Press
ISBN: 1139458108
Category : Science
Languages : en
Pages : 231
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Book Description
This book presents a full spectrum of views on current approaches to modeling cell mechanics. The authors come from the biophysics, bioengineering and physical chemistry communities and each joins the discussion with a unique perspective on biological systems. Consequently, the approaches range from finite element methods commonly used in continuum mechanics to models of the cytoskeleton as a cross-linked polymer network to models of glassy materials and gels. Studies reflect both the static, instantaneous nature of the structure, as well as its dynamic nature due to polymerization and the full array of biological processes. While it is unlikely that a single unifying approach will evolve from this diversity, it is the hope that a better appreciation of the various perspectives will lead to a highly coordinated approach to exploring the essential problems and better discussions among investigators with differing views.
Author:
Publisher: Elsevier
ISBN: 0444636420
Category : Medical
Languages : en
Pages : 448
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Book Description
Brain Banking, Volume 150, serves as the only book on the market offering comprehensive coverage of the functional realities of brain banking. It focuses on brain donor recruitment strategies, brain bank networks, ethical issues, brain dissection/tissue processing/tissue dissemination, neuropathological diagnosis, brain donor data, and techniques in brain tissue analysis. In accordance with massive initiatives, such as BRAIN and the EU Human Brain Project, abnormalities and potential therapeutic targets of neurological and psychiatric disorders need to be validated in human brain tissue, thus requiring substantial numbers of well characterized human brains of high tissue quality with neurological and psychiatric diseases. Offers comprehensive coverage of the functional realities of brain banking, with a focus on brain donor recruitment strategies, brain bank networks, ethical issues, and more Serves as a valuable resource for staff in existing brain banks by highlighting best practices Enhances the sharing of expertise between existing banks and highlights a range of techniques applicable to banked tissue for neuroscience researchers Authored by leaders from brain banks around the globe – the broadest, most expert coverage available
Author: Wayne S. Sossin
Publisher: Oxford University Press
ISBN: 0190686324
Category : Science
Languages : en
Pages : 512
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Book Description
Translational control in the nervous system is important. Many physiological processes in the nervous system depend on accurate control of the proteome that is mediated through protein synthetic mechanisms and thus, the nervous system is very sensitive to dysregulation of translational control. The Oxford Handbook of Neuronal Protein Synthesis reviews the mechanisms of translational control used by the nervous system, as well as how important nervous system functions, such as plasticity and homeostasis, depend on accurate translational control. The handbook extensively covers how dysregulation of protein synthesis can manifest itself in many distinct pathological processes including neurodevelopmental, neuropsychiatric, and neurodegenerative diseases. The handbook is comprehensive in its coverage of translational control mechanisms with particular focus on how these general control mechanisms are specifically utilized in the context of the cell biological constraints of the nervous system from both a mechanistic and systems perspective.
