Non-fibrillar Amyloidogenic Protein Assemblies - Common Cytotoxins Underlying Degenerative Diseases

574 Pages·2012·8.48 MB·English

by  Farid Rahimi

Non-fi brillar Amyloidogenic Protein
Assemblies—Common Cytotoxins Underlying
Degenerative Diseases

Farid Rahimi • Gal Bitan
Editors
Non-fi brillar Amyloidogenic
Protein Assemblies—
Common Cytotoxins
Underlying Degenerative
Diseases
Editors
Farid Rahimi Gal Bitan
Research School of Biology Neurology
Australian National University University of California at Los Angeles
Linnaeus Way Charles E. Young Drive South 635
Canberra, ACT 0200 Los Angeles, CA 90095-7334
Australia USA
[email protected] [email protected]
ISBN 978-94-007-2773-1 e-ISBN 978-94-007-2774-8
DOI 10.1007/978-94-007-2774-8
Springer Dordrecht Heidelberg London New York
Library of Congress Control Number: 2011944432
© Springer Science+Business Media B.V. 2012
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Preface
Amyloid is a fascinating phenomenon. Proteins that have been shaped by millions
of years of evolution lose their structure, if they had one, and gain a new structure,
in which regardless of their amino acid sequence, they form tightly bound “one-
dimensional” arrays of indefi nite length and become insoluble. This new form of
the protein typically is abnormal and is associated with various diseases, though in
some cases, the amyloid form is functional and used in normal physiology.
The relationship between presence of amyloid and etiology of disease has
been the subject of numerous studies and has caused much debate in the scientifi c
community. An important realization that gradually has been taking hold in our
understanding of this relationship is that the amyloid may be a hallmark of each
disease but not necessarily the cause of the disease. Rather, oligomers of amyloid-
forming proteins likely are the real perpetrators of the cytotoxicity that is character-
istic of all amyloid-related diseases. Such oligomers typically are thought of as
precursors of the amyloid, but in some cases have been observed to form down
separate folding and assembly pathways. Therefore, we refer to them generally as
non-fi brillar protein assemblies.
It has been our pleasure to serve as editors of Non-fi brillar Amyloidogenic Protein
Assemblies—Common Cytotoxins Underlying Degenerative Diseases . We hope that
this compilation of reviews will serve as a resource for researchers, students, and
industry and medical professionals who are interested in the phenomenon of amy-
loid, the particular proteins discussed in the book, and the associated degenerative
diseases.
The book begins with our historical account of the term amyloid , an introduction
to fi brillar and non-fi brillar assemblies and their toxicity, and a discussion of often-
overlooked methodological and experimental challenges in studying amyloid
diseases. In Chap. 2 , Vinters et al. illustrate the neuropathologic features of
Alzheimer’s disease and several non-Alzheimer dementias. Chapter 3 by Frydman-
Marom et al. details the methods used for characterization of various oligomeric
protein assemblies and reviews methods used to prepare these assemblies in vitro.
The following ten chapters are dedicated to specifi c amyloidogenic proteins and the
diseases associated with them. In Chap. 4 , Wilcox and coworkers cover biological
v
vi Preface
targeting and activity of amyloid b -protein assemblies in Alzheimer’s disease and
highlight the interconnections between Alzheimer’s disease and insulin signaling in
the aging brain. In Chap. 5 , Bhaskar and Lamb highlight different aspects of the
proteins related to Alzheimer’s disease and discuss studies on formation and detec-
tion of toxic assemblies of amyloid b -protein and t protein, summarizing the current
evidence on how these proteins cause neurotoxicity.
Chapter 6 by Hong et al. recounts illustrative examples of soluble, toxic or non-toxic
amyloid oligomers and emphasize the roles of soluble oligomers of a -synuclein in
the pathogenesis of Parkinson’s disease.
Degaki et al. in Chap. 7 report various aspects of cytotoxicity of islet amyloid
polypeptide in the pathogenesis of type-2 diabetes mellitus. Kerman and Chakrabartty
elucidate key structural features of the misfolded superoxide dismutase 1 and its
potential toxic effects in amyotrophic lateral sclerosis, in Chap. 8 .
Chapters 9 and 10 by Legname et al. and Morales et al. discuss misfolding of
prions and prion diseases. Murphy et al., in Chap. 11 , review the roles of expanded
polyglutamine proteins in neurodegeneration. In Chaps. 12 and 13 , Hodkinson et al.
and Saraiva et al. describe the roles of b -microglobulin and transthyretin in dialysis-
2
related amyloidosis and familial amyloid polyneuropathy, respectively. In the closing
chapter of the book, Lanning and Meredith comprehensively review therapeutic
strategies for inhibiting abnormal protein self-assembly.
We are grateful to the scholars who dedicated their time and energy and contributed
the different chapters of the book. We acknowledge and thank all the international
experts who served as peer reviewers. Creation of this book would not have been
possible without their contributions.
Farid Rahimi and Gal Bitan
Contents
1 Overview of Fibrillar and Oligomeric Assemblies
of Amyloidogenic Proteins. ..................................................................... 1
Farid Rahimi and Gal Bitan
2 Pathologic Lesions in Alzheimer Disease
and Other Neurodegenerative Diseases—Cellular
and Molecular Components ................................................................... 37
Harry V. Vinters, M.D., F.A.C.P., F.R.C.P.C, Spencer Tung, B.S., and
Orestes E. Solis, M.D.
3 Preparation and Structural Characterization of Pre-fi brillar
Assemblies of Amyloidogenic Proteins .................................................. 61
Anat Frydman-Marom, Yaron Bram, and Ehud Gazit
4 Biological Targeting and Activity of Pre-fi brillar Ab Assemblies ...... 103
Kyle C. Wilcox, Jason Pitt, Adriano Sebollela, Helen Martirosova,
Pascale N. Lacor, and William L. Klein
5 The Role of A b and Tau Oligomers in the Pathogenesis
of Alzheimer’s Disease ............................................................................ 135
Kiran Bhaskar and Bruce T. Lamb
6 Oligomers of a -Synuclein in the Pathogenesis
of Parkinson’s Disease ............................................................................ 189
Dong-Pyo Hong, Wenbo Zhou, Aaron Santner,
and Vladimir N. Uversky
7 Cytotoxic Mechanisms of Islet Amyloid Polypeptide
in the Pathogenesis of Type-2 Diabetes Mellitus (T2DM) ................... 217
Theri Leica Degaki, Dahabada H. J. Lopes, and Mari Cleide Sogayar
8 Protein Misfolding and Toxicity in Amyotrophic
Lateral Sclerosis ...................................................................................... 257
Aaron Kerman and Avijit Chakrabartty
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viii Contents
9 Structural Studies of Prion Proteins and Prions .................................. 289
Giuseppe Legname, Gabriele Giachin, and Federico Benetti
10 Role of Prion Protein Oligomers in the Pathogenesis
of Transmissible Spongiform Encephalopathies .................................. 319
Rodrigo Morales, Claudia A. Duran-Aniotz, and Claudio Soto
11 When More Is Not Better: Expanded Polyglutamine
Domains in Neurodegenerative Disease ................................................ 337
Regina M. Murphy, Robert H. Walters, Matthew D. Tobelmann,
and Joseph P. Bernacki
12 Protein Misfolding and Toxicity in Dialysis-Related
Amyloidosis .............................................................................................. 377
John P. Hodkinson, A lison E. Ashcroft, and Sheena E. Radford
13 Transthyretin Aggregation and Toxicity ............................................... 407
Maria João Saraiva and Isabel Santos Cardoso
14 Strategies for Inhibiting Protein Aggregation:
Therapeutic Approaches to Protein-Aggregation Diseases ................. 433
Jennifer D. Lanning and Stephen C. Meredith
Index ................................................................................................................. 561
Chapter 1
Overview of Fibrillar and Oligomeric
Assemblies of Amyloidogenic Proteins
Farid Rahimi and Gal Bitan
Abstract Aberrantly folded proteins are implicated in over 40 human

diseases, including neurodegenerative diseases such as Alzheimer’s, Parkinson’s,
Huntington’s, and Creutzfeldt–Jakob diseases; diseases of particular organs,
including desmin-related cardiomyopathy or type-2 diabetes mellitus; and systemic
diseases, such as senile systemic amyloidosis or light-chain amyloidosis. Although
the proteins involved in each disease have unrelated sequences and dissimilar native
structures, they all undergo conformational alterations and “misfold” to form fi bril-
lar polymers characterized by a cross-b structure. Fibrillar assemblies build up pro-
gressively into intracellular or extracellular proteinaceous aggregates generating the
pathognomonic amyloid-like lesions i n vivo. Substantial evidence accumulated in
the last decade suggest, that in many amyloid-related diseases, the lesions contain-
ing the protein aggregates are the end state of aberrant protein folding whereas the
actual culprits causing the disease are soluble, non-fi brillar assemblies preceding
the insoluble aggregates. The non-fi brillar protein assemblies are diverse and range
from small, low-order oligomers to large assemblies, including spherical, annular,
and protofi brillar species. Oligomeric species with different degrees of structural
order are believed to mediate various pathogenic mechanisms that may lead to
F. Rahimi (*)
Research School of Biology, Division of Biomedical Science and Biochemistry,
College of Medicine, Biology, and Environment , The Australian National University ,
Canberra , ACT , Australia
e-mail: [email protected]
G. Bitan (*)
Department of Neurology , David Geffen School of Medicine; Brain Research Institute;
and Molecular Biology Institute, University of California at Los Angeles ,
635 Charles E. Young Drive South, Los Angeles , CA 90025 , USA
e-mail: [email protected]
F. Rahimi and G. Bitan (eds.), Non-fi brillar Amyloidogenic Protein Assemblies—Common 1
Cytotoxins Underlying Degenerative Diseases, DOI 10.1007/978-94-007-2774-8_1,
© Springer Science+Business Media B.V. 2012