Protein Misfolding Disorders: A Trip into the ER


by

Claudio Hetz

DOI: 10.2174/97816080501301090101
eISBN: 978-1-60805-013-0, 2009
ISBN: 978-1-60805-575-3

  
  


Indexed in: Scopus

Neurodegenerative disorders such as Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease (AD), Parkinson’s disease (PD), Prion-re...[view complete introduction]
PDF US $
- Single user / Non-Library usage: 59
- Multi user / Library usage: 236
Print-On-Demand (P.O.D): *71
Special Offer for Single user / Non-Library usage (PDF + P.O.D): *100

*(Excluding Mailing and Handling)
Purchase: Book Chapters
Download Flyers

Table of Contents

Foreword , Pp. i

Laurie H. Glimcher
Download Free

Preface , Pp. ii-iii (2)

Claudio Hetz
Download Free

Contributors , Pp. iv-vi (3)

Claudio Hetz
Download Free

Targeting Endoplasmic Reticulum Stress Pathways to Treat Neurological Disorders Associated with Protein Misfolding , Pp. 1-18 (18)

Danny Galleguillos, Soledad Matus, Vicente Valenzuela, Pamela Valdes, Alexis Martinez, Melissa Nassif, Mauricio Torres, Gabriela Martinez and Claudio Hetz
Purchase Chapter

The Unfolded Protein Response in Mammalian Cells , Pp. 19-46 (28)

Sung Hoon Back, Justin R. Hassler and Randal J. Kaufman
Purchase Chapter

The ER Chaperone GRP78 and Cancer , Pp. 47-55 (9)

Risheng Ye, Yi Zhang and Amy S. Lee
Purchase Chapter

Endoplasmic Reticulum Stress and Protein Misfolding in Amyotrophic Lateral Sclerosis , Pp. 56-76 (21)

A. K. Walker, B. J. Turner and J. D. Atkin
Purchase Chapter

ER Stress Signaling Network in Pancreatic β-Cells , Pp. 77-87 (11)

Sonya G. Fonseca and Fumihiko Urano
Purchase Chapter

Heritable Neurodevelopmental Disorders and Endoplasmic Reticulum Stress , Pp. 88-93 (6)

Takashi Momoi and Eriko Fujita
Purchase Chapter

ER Quality Control, ER Stress-Induced Apoptosis, and Neurodegenerative Diseases , Pp. 94-102 (9)

Hideki Nishitoh, Hisae Kadowaki, Kohsuke Takeda and Hidenori Ichijo
Purchase Chapter

Role of Alzheimer’s β-Amyloid on Wnt Signaling , Pp. 103-113 (11)

Nibaldo C. Inestrosa, Catalina Grabowski, Macarena Arrazola, Lorena Varela-Nallar and Enrique M. Toledo
Purchase Chapter

β-Amyloid Peptide, Endoplasmic Reticulum Stress, and Alzheimer’s Disease , Pp. 114-126 (13)

Othman Ghribi
Purchase Chapter

Endoplasmic Reticulum Stress Response in Prion Diseases , Pp. 127-135 (9)

Abhisek Mukherjee and Claudio Soto
Purchase Chapter

Autophagy and the Ubiquitin-Proteasome System - Protein Catabolism Comes Full Circle , Pp. 136-147 (12)

Natalia B. Nedelsky and J. Paul Taylor
Purchase Chapter

Foreword

Secretory cells require an expanded endoplasmic reticulum (ER) to carry out their task. Efficient protein folding inevitably leads to the accumulation of misfolded proteins as well, a normal byproduct of the protein maturation process. Hence, specialized secretory activity is accompanied by constant ER stress, constituting a threat to the life of a cell. Adaptation to the stress of protein misfolding is accomplished by the activation of a complex signaling pathway known as the unfolded protein response (UPR). Genetic manipulation of the UPR supports the notion that components of the pathway are essential to sustain the function of secretory cells such as B lymphocytes and pancreatic exocrine and endocrine cells.

Emerging evidence suggests that the occurrence of ER stress influences diseases ranging from cancer to autoimmunity and diabetes. Perturbation in organelle function has also been observed in many neurological disorders related to protein misfolding and aggregation. Most neurodegenerative disorders share a common neuropathology, primarily featuring the presence of abnormal protein aggregates containing specific misfolded proteins. These diseases include pathological conditions such as amyotrophic lateral sclerosis (ALS), Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Prion-related Disorders (PrD), Huntington’s Disease (HD), and others.

In this informative e-Book, Claudio Hetz has brought together experts in the UPR to provide an overview of the emerging role of ER stress and protein misfolding in different physiological and pathological conditions. Several chapters focus on the role of the UPR in specific diseases such as diabetes, cancer, and neurodegeneration; other chapters discuss biochemical and genetic mechanisms underpinning the UPR, autophagy and the ubiquitin-proteasome system. Auhors include Amy Lee, an expert in chaperone biology and cancer; Randal Kaufman, a pioneer in identifying the components of the UPR; Claudio Soto, Hidenori Hichijo, and Takashi Momoi, experts in neurodegeneration and protein misfolding, and many others. An important focus of the book is considering the potential therapeutic benefits of targeting ER stress pathways in the context of human disease. Readers interested in understanding how a cell handles protein folding stress and the consequences of dysregulation of this process for human disease will find this book invaluable.

Laurie H. Glimcher, M.D
Irene Heinz Given
Professor of Immunology
Harvard School of Public Health
Professor of Medicine
Harvard Medical School


Preface

The functional and structural integration between different subcellular compartments is essential for the proper function of a cell. At each organelle, different molecular sentinels permanently sense stressful cellular conditions and initiate complex responses that aim either to adapt to the new conditions restoring homeostasis, or to induce cell suicide to eliminate the damaged cell. One particular organelle, the endoplasmic reticulum (ER), had merged as a main subcellular compartment affected in diverse pathological conditions as diverse as cancer, diabetes, and brain disorders. The ER has important roles in physiology including regulating and executing many post-translational modifications of proteins, ensuring their proper folding and facilitating formation of functional protein complexes. The ER is also the place where the biosynthesis of steroids, cholesterol, and other lipids occurs, playing a crucial role in organelle biogenesis and signaling through the generation of lipid second messengers. The ER is well-known as a major calcium store in the cells and thus constitutes a signaling organelle that modulates many cellular processes including proliferation, cell death and differentiation via calcium release.

A number of physiological and pathological conditions alter the protein folding status at the ER, leading to the accumulation of unfolded or misfolded proteins in the ER lumen, a cellular condition referred as “ER stress”. ER stress triggers a complex adaptive reaction known as the unfolded protein response (UPR), which aims the restoration of the homeostasis of this organelle. Activation of the UPR affects the expression of proteins involved in nearly every aspect of the secretory pathway, including protein entry into the ER, folding, glycosylation, ER-associated degradation (ERAD), ER biogenesis, lipid metabolism and vesicular trafficking. The UPR restores the folding capacity to decrease unfolded protein load. Different physiological conditions can induce the UPR by increasing the demand of protein synthesis/secretion or by the generation of excessive misfolded proteins as described for B lymphocytes and pancreatic β cells. Also, abnormal metabolic conditions, such as glucose deprivation can trigger the UPR. Components of the ER stress pathway have been shown to be an important factor for tumor survival and growth due to an adaptation to hypoxia conditions. In addition, in different neurodegenerative conditions associated with protein misfolding (including Huntington's disease, Alzheimer's, Prion-related disorders, amyotrophic lateral sclerosis and others), an irreversible alteration of ER homeostasis has been proposed to be a critical mediator of neuronal dysfunction.

In this book we put together many specialized chapters discussing the emerging role of ER stress and protein misfolding in diverse pathologies. Dr. Fumico Urano from UMASS gives a comprehensive summary of the experimental data supporting the role of the UPR in diabetes. Crucial mediators in the alleviation of the stress in the ER are protein chaperones and foldases of the Glucose Regulated Protein (GRPs) family. Amy Lee, one of the pioneers in the study of GRPs in apoptosis and ER stress, presents an overview of the multiple functional roles of this family of proteins in cancer. Randal Kaufman, a recognized pioneer in the field, prepared a detailed analysis of the function and interconnection between different UPR signaling pathways.

Accumulation of abnormal protein aggregates composed of misfolded proteins is a common denominator in many neurological disorders. Diferent specialist in diverse neurological disorders, including Drs. Julie Atkin, Hidenori Hichijo, Takashi Momoi, Othman Ghribi, Nibaldo Inestrosa, Claudio Soto, and myself, discuss recent evidences suggesting the involvement of ER stress and other signaling pathways in protein misfolding disorders affecting the nervous system and the possible therapeutic benefits of targeting the UPR. As the reader will conclude from this selected group of chapters, pharmacological targeting of different components of the UPR/ER stress pathway may have therapeutic application for the treatment of many pathological conditions, such as diabetes, cancer and neurological disorders.

Claudio Hetz, PhD
Director Laboratory Cellular Stress and Biomedicine
Institute of Biomedical Sciences
University of Chile
Santiago, Chile.
and Adjunct Professor
Harvard School of Public Health
Boston, USA

List of Contributors

Editor(s):
Claudio Hetz
Institute of Biomedical Sciences, University of Chile
Chile




Contributor(s):
Claudio Hetz
Institute of Biomedical Sciences University of Chile
Independencia 1027 P.O. BOX 70086
Santiago
Chile


Randal J. Kaufman
University of Michigan Medical Center
Howard Hughes Medical Institute
Ann Arbor
MI , 48109-0650
USA


Amy S Lee
USC/Norris Comprehensive Cancer Center
University of Southern California Keck School of Medicine
Los Angeles
California , 90089
USA


J.D. Atkin
University of Melbourne
Howard Florey Institute
Parkville
Victoria, 3010
Australia


Fumihiko Urano
University of Massachusetts Medical School
Worcester
MA , 01605
USA


Takashi Momoi
Divisions of Development and Differentiation Department of Human Inherited Metabolic Disease
National Institute of Neuroscience
4-1-1 Ogawahigashi-machi
Kodaira
Tokyo , 187-8502
Japan


Hidenori Ichijo
Cell Signaling Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo Bunkyo-ku
Bunkyo-ku
Tokyo , 113-0033
Japan


Nibaldo C. Inestrosa
Centro de Envejecimiento y Regeneración (CARE) Facultad de Ciencias Biológicas
Pontificia Universidad Católica de Chile
Santiago
Chile


Othman Ghribi
Department of Pharmacology Physiology and Therapeutics
University of North Dakota School of Medicine
Grand Forks
ND, 58202
USA


Claudio Soto
Protein Misfolding Disorders Laboratory, Dept of Neurology
George and Cynthia Mitchell Center for Neurodegenerative Diseases, University of Texas Medical School at Houston
USA


J. Paul Taylor
Department of Developmental Neurobiology
St. Jude Children’s Research Hospital
262 Danny Thomas Place
Memphis
TN , 38120
USA


Danny Galleguillos
FONDAP Center for Molecular Studies of the Cell
University of Chile
Independencia 1027
Santiago
Chile


Vicente Valenzuela
FONDAP Center for Molecular Studies of the Cell
University of Chile
Independencia 1027
Santiago
Chile


Pamela Valdés
FONDAP Center for Molecular Studies of the Cell
University of Chile
Independencia 1027
Santiago
Chile


Alexis Martínez
FONDAP Center for Molecular Studies of the Cell
University of Chile
Independencia 1027
Santiago
Chile


Soledad Matus
FONDAP Center for Molecular Studies of the Cell
University of Chile
Independencia 1027
Santiago
Chile


Melissa Nassif
FONDAP Center for Molecular Studies of the Cell
University of Chile
Independencia 1027
Santiago
Chile


Mauricio Torres
FONDAP Center for Molecular Studies of the Cell
University of Chile
Independencia 1027
Santiago
Chile


Gabriela Martínez
FONDAP Center for Molecular Studies of the Cell
University of Chile
Independencia 1027
Santiago
Chile


Sung Hoon Back
Howard Hughes Medical Institute University of Michigan Medical Center
Ann Arbor
MI , 48109-0650
USA


Justin R. Hassler
Howard Hughes Medical Institute University of Michigan Medical Center
Ann Arbor
MI , 48109-0650
USA


Risheng Ye
University of Southern California Keck School of Medicine
Los Angeles
California , 90089
USA


Yi Zhang
University of Southern California Keck School of Medicine
Los Angeles
California , 90089
USA


Sonya G. Fonseca
University of Massachusetts Medical School
Worcester
MA , 01605
USA


A.K. Walker
Howard Florey Institute University of Melbourne
Parkville
Victoria , 3010
Australia


B.J. Turner
Howard Florey Institute University of Melbourne
Parkville
Victoria , 3010
Australia


Eriko Fujita
Divisions of Development and Differentiation Department of Human Inherited Metabolic Disease
National Institute of Neuroscience
4-1-1 Ogawahigashi-machi
Kodaira
Tokyo , 87-8502
Japan


Hideki Nishitoh
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Tokyo , 113-0033
Japan


Hisae Kadowaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Tokyo, 113-0033
Japan


Kohsuke Takeda
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Tokyo , 113-0033
Japan


Catalina Grabowski
Centro de Envejecimiento y Regeneración (CARE) Facultad de Ciencias Biológicas
Pontificia Universidad Católica de Chile
Santiago
Chile


Macarena Arrázola
Centro de Envejecimiento y Regeneración (CARE) Facultad de Ciencias Biológicas
Pontificia Universidad Católica de Chile
Santiago
Chile


Lorena Varela-Nallar
Centro de Envejecimiento y Regeneración (CARE) Facultad de Ciencias Biológicas
Pontificia Universidad Católica de Chile
Santiago
Chile


Enrique M. Toledo
Centro de Envejecimiento y Regeneración (CARE) Facultad de Ciencias Biológicas
Pontificia Universidad Católica de Chile
Santiago
Chile


Abhisek Mukherjee
Protein Misfolding Disorders Laboratory
George and Cynthia Mitchell Center for Neurodegenerative Diseases
USA


Natalia B. Nedelsky
Department of Developmental Neurobiology
St. Jude Children’s Research Hospital
262 Danny Thomas Place
Memphis
TN , 38120
USA




Advertisement


Webmaster Contact: urooj@benthamscience.org Copyright © 2014 Bentham Science