Tài liệu Intracellular Traffic and Neurodegenerative Disorders pptx

Intracellular Traffic and Neurodegenerative

Disorders

RESEARCH AND PERSPECTIVES IN ALZHEIMER’S DISEASE

Peter H. St. George-Hyslop • William C. Mobley

Yves Christen

Editors

Intracellular Traffic

and Neurodegenerative

Disorders

123

Editors

Dr. Peter H. St. George-Hyslop

Department of Laboratory Medicine

and Pathobiology

University of Toronto

Tranz Neuroscience Bldg.

Toronto ON M5S 3H2

Canada

[email protected]

Dr. Yves Christen

Fondation IPSEN

Pour la Recherche Thérapeutique

65, quai Georges Gorse

92650 Boulogne Billancourt

Cedex - France

[email protected]

Dr. William C. Mobley

Department of Neurology

Standford University School of Medicine

Standford CA 94305-5316

USA

[email protected]

ISSN 0945-6066

ISBN 978-3-540-87940-4 e-ISBN 978-3-540-87941-1

Library of Congress Control Number: 2008936139

c 2009 Springer-Verlag Berlin Heidelberg

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Foreword

Neurodegenerative disorders are common and devastating. Rationally, the most

effective treatments will target pathogenetic mechanisms. While alternative ap￾proaches, based on alleviating the symptoms of patients with Alzheimer disease,

Parkinson disease, Huntington disease, prion disorders or amyotrophic lateral scle￾rosis, can be expected to reduce suffering, studies of pathogenesis of these age￾related disorders will be most important for enabling early diagnosis and the creation

of preventative and curative treatments. It is in this context that a recent IPSEN

meeting (The 23rd Colloque Medecine et Recherche ´ , April 28, 2008) focused on

a role for disruption of intracellular trafficking in neurodegenerative disorders. The

meeting captured emerging insights into pathogenesis from disrupted trafficking and

processing of proteins implicated in age-related degeneration.

Protein folding, trafficking and signaling were the principal topics covered at

the meeting. Importantly, the presenters pointed to the importantly intersection of

these themes. While the proteolytic processing of APP into its toxic product, the

Aβ peptide, is an intensive focus of work in many laboratories, it is only relatively

recently that investigators have begun to examine in depth the cellular compartments

and trafficking events that mediate APP processing and how derangement of traf￾ficking pathways could impact them. Thus, discoveries by St George-Hyslop and

colleagues that SORL1 binds APP, that certain polymorphisms in SORL1 increases

the risk of Alzheimer disease and that several of these polymorphisms are predicted

to modify SORL1 levels so as to increase Aβ production provided the perspective

that malfunction of cellular mechanisms could play a defining role in APP-linked

pathology. Willnow built on this theme by defining further the cellular pathways

impacted by SORLA, while Seaman linked these observations with proteins of the

retromer complex, for which earlier evidence suggested a link to altered APP pro￾cessing. Contributions by Beyreuther and Kins and by Haass further informed the

discussion by providing new insights into the proteins with which APP interacts,

including its family members APLP1 and 2, and through studies of g secretase.

Gandy reviewed studies showing that APP sorting and metabolism is informed by

a number of extracellular signals that act through phosphorylation of APP. Impor￾tantly, the participation of the endosomal pathway and early endosomes in particular

v

vi Foreword

reinforce the view that trafficking errors at this locus contribute significantly to

APP-linked pathology, observations addressed directly by Rajendran and Simons.

Sorkin detailed recent advances in understanding protein trafficking and signaling

in the endosomal system, studies that must now be extended to APP. But what is

it about APP misprocessing that defines key steps in pathogenesis? Most investiga￾tors focus squarely on Aβ, but recent findings suggest that a more refined focus on

APP will be needed to understand important steps. Indeed, Mobley and colleagues,

in studies of mouse models of Down syndrome, show that APP gene dose, and

particularly the levels of its C-terminal fragments, may be more directly linked to

Alzheimer-like pathogenesis than the level of the Aβ peptide. By what mechanisms

would altered trafficking mechanisms influence the cell? An emerging theme, one

that links studies of Alzheimer pathogenesis to other neurodegenerative disorders, is

that protein misfolding plays a defining role. This was the focus of work reported by

Lindquist, in studies of Parkinson and Huntington disease models, and Mandelkow

and colleagues in studies of tau mutants. The ability of misfolded proteins to dysreg￾ulate cellular processes raises the exciting possibility that protein misfolding errors

can be defined and serve as a target of future therapeutics. In the end, it will be

essential to explore the events whose compromise is critical to neural cell survival

and function. One important lesion may be the axonal transport of trophic messages.

Holzbauer makes a compelling case that such messages are markedly compromised

in models of amyotrophic lateral sclerosis and Saudou documents dramatic changes

in BDNF trafficking in models of Huntington disease. Finally, Mobley reports dis￾ruption of NGF transport in models of Down syndrome and Alzheimer disease. That

other important retrograde messages must be examined is suggested by Martin and

colleagues who document the dynamic processes that link axonal transport with

synaptic plasticity.

Though it is difficult to predict the course of future work, the meeting supported

the view that misregulation of processing and trafficking events, especially those

that occur in the endocytic pathway, will be important for defining and countering

the pathogenesis of age-related neurodegenerative disorders.

W. Mobley

P. St George-Hyslop

Y. Christen

Acknowledgements

The editors wish to thank Jacqueline Mervaillie and Sonia Le Cornec for the

organization of the meeting and Mary Lynn Gage for the editing of the book.

vii

Contents

Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xi

Amyloid Precursor Protein Sorting and Processing: Transmitters,

Hormones, and Protein Phosphorylation Mechanisms ................. 1

Sam Gandy, Odete da Cruz e Silva, Edgar da Cruz e Silva,

Toshiharu Suzuki, Michelle Ehrlich, and Scott Small

Intramembrane Proteolysis by γ-Secretase and Signal Peptide Peptidases 11

Regina Fluhrer and Christian Haass

Axonal Transport and Neurodegenerative Disease .................... 27

Erika L. F. Holzbaur

Simple Cellular Solutions to Complex Problems ...................... 41

Susan Lindquist and Karen L. Allendoerfer

Tau and Intracellular Transport in Neurons ......................... 59

E.-M. Mandelkow, E. Thies, S. Konzack, and E. Mandelkow

Signaling Between Synapse and Nucleus During Synaptic Plasticity ..... 71

Kwok-On Lai, Dan Wang, and Kelsey C. Martin

Axonal Transport of Neurotrophic Signals: An Achilles’ Heel

for Neurodegeneration? .......................................... 87

Ahmad Salehi, Chengbiao Wu, Ke Zhan, and William C. Mobley

Membrane Trafficking and Targeting in Alzheimer’s Disease ........... 103

Lawrence Rajendran and Kai Simons

Huntington’s Disease: Function and Dysfunction of Huntingtin

in Axonal Transport ............................................. 115

Fr´ed´eric Saudou and Sandrine Humbert

ix

x Contents

The Role of Retromer in Neurodegenerative Disease .................. 125

Claire F. Skinner and Matthew N.J. Seaman

Regulation of Endocytic Trafficking of Receptors and Transporters

by Ubiquitination: Possible Role in Neurodegenerative Disease ......... 141

Alexander Sorkin

The Sortilin-Related Receptor SORL1 is Functionally and Genetically

Associated with Alzheimer’s Disease ............................... 157

Ekaterina Rogaeva, Yan Meng, Joseph H. Lee, Richard Mayeux,

Lindsay A. Farrer, and Peter St George-Hyslop

Regulation of Transport and Processing of Amyloid Precursor Protein

by the Sorting Receptor SORLA ................................... 167

Thomas E. Willnow, Michael Rohe, and Vanessa Schmidt

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 181

Contributors

Allendoerfer Karen L.

Whitehead Institute for Biomedical Research and Howard Hughes Medical

Institute, 9 Cambridge Center, Cambridge MA 02142, USA

da Cruz e Silva Edgar

Centro de Biologia Celular, University of Aveiro, Aveiro, Portugal

da Cruz e Silva Odete

Centro de Biologia Celular, University of Aveiro, Aveiro, Portugal

Ehrlich Michelle

Mount Sinai School of Medicine

New York NY 10029

Farrer Lindsay A.

Departments of Medicine (Genetics Program), Neurology, Genetics & Genomics,

Epidemiology, and Biostatistics, Boston University Schools of Medicine and Public

Health, Boston MA 02118, USA

Fluhrer Regina

Center for Integrated Protein Science Munich and Adolf-Butenandt-Institute,

Department of Biochemistry, Laboratory for Neurodegenerative Disease Research,

Ludwig-Maximilians-University, 80336 Munich, Germany

Gandy Samuel E.

Mount Sinai School of Medicine

New York NY 10029

[email protected]

Haass Christian

Center for Integrated Protein Science Munich and Adolf-Butenandt-Institute,

Department of Biochemistry, Laboratory for Neurodegenerative

Disease Research, Ludwig-Maximilians-University, 80336 Munich, Germany,

[email protected]

xi

xii Contributors

Holzbaur Erika L.F.

Department of Physiology, University of Pennsylvania School of Medicine,

D400 Richards Building, 3700 Hamilton Walk, Philadelphia PA 19104, USA,

[email protected]

Humbert Sandrine

UMR 146 CNRS, Institut Curie, Bˆatiment 110-Centre Universitaire, 91405 Orsay,

France

Konzack S.

Max-Planck-Unit for Structural Molecular Biology, c/o DESY, Notkestrasse 85,

22607 Hamburg, Germany

Lai Kwok-On

Department of Psychiatry and Biobehavioral Sciences, Brain Research Institute,

UCLA, BSRB 390B, 615 Charles E. Young Dr. S., Los Angeles CA 90095-1737,

USA

Lee Joseph H.

The Taub Institute on Alzheimer’s Disease and the Aging Brain, The Gertrude H.

Sergievsky Center, College of Physicians Surgeons, Department of Epidemiology,

Mailman School of Public Health, Columbia University, New York, USA

Lindquist Susan

Whitehead Institute for Biomedical Research and Howard Hughes

Medical Institute, 9 Cambridge Center, Cambridge MA 02142, USA,

lindquist [email protected]

Mandelkow Eckhard

Max-Planck-Unit for Structural Molecular Biology, c/o DESY, Notkestrasse 85,

22607 Hamburg, Germany

Mandelkow Eva-Maria

Max-Planck-Unit for Structural Molecular Biology, c/o DESY, Notkestrasse 85,

22607 Hamburg, Germany, [email protected]

Martin Kelsey

Department of Psychiatry and Biobehavioral Sciences, Brain Research Institute,

Department of Biological Chemistry, Semel Institute for Neuroscience and Human

Behavior, UCLA, BSRB 390B, 615 Charles E. Young Dr. S., Los Angeles CA

90095-1737 USA, [email protected]

Mayeux Richard

The Taub Institute on Alzheimer’s Disease and the Aging Brain, The Gertrude H.

Sergievsky Center, College of Physicians Surgeons, Department of Epidemiology,

Mailman School of Public Health, Columbia University, New York, USA

Contributors xiii

Meng Yan

Departments of Medicine (Genetics Program), Neurology, Genetics & Genomics,

Epidemiology, and Biostatistics, Boston University Schools of Medicine and Public

Health., Boston MA 02118, USA

Mobley William

Department of Neurology, MSLS, P205, Stanford University School of Medicine,

300 Pasteur Drive Stanford CA 94305, USA, [email protected]

Rajendran Lawrence

Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse

108, 01307 Dresden, Germany, [email protected]

Rogaeva Ekaterina

Centre for Research in Neurodegenerative Diseases, Departments of Medicine,

Laboratory Medicine and Pathobiology, Medical Biophysics, University of Toronto,

and Toronto Western Hospital Research Institute, Toronto, Ontario, Canada

Rohe Michael

Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany

Salehi Ahmad

Stanford University School of Medicine, Dept of Neurology, Stanford CA 94305,

USA, [email protected]

Saudou Fred´ eric ´

UMR 146 CNRS, Institut Curie, Bˆatiment 110-Centre Universitaire, 91405 Orsay,

France, [email protected]

Schmidt Vanessa

Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany

Seaman Matthew

Department of Clinical Biochemistry, Cambridge Institute for Medical Research,

Wellcome Trust & MRC Building, Addenbrookes Hospital, Hills Road, Cambridge

CB2 2XY, UK, [email protected]

Simons Kai

Max Planck Institute of Molecular Cell Biology and Genetics, Pfotenhauerstrasse

108, 01307 Dresden, Germany, [email protected]

Skinner Claire F.

Department of Clinical Biochemistry, Cambridge Institute for Medical Research,

Wellcome Trust & MRC Building, Addenbrookes Hospital, Hills Road, Cambridge

CB2 2XY, UK

Small Scott

Columbia University College of Physicians and Surgeons,

New York NY 10032, USA

xiv Contributors

Sorkin Alexander

Department of Pharmacology, University of Colorado at Denver and Health,

Sciences Center, Room 6115, Research Complex 1, 12800 East 19th Avenue,

Aurora CO 80045, USA, [email protected]

St George-Hyslop Peter

Centre for Research in Neurodegenerative Diseases, Departments of Medicine,

Laboratory Medicine and Pathobiology, Medical Biophysics, University of Toronto,

and Toronto Western Hospital Research Institute, Toronto, Ontario, Canada and

Cambridge Institute for Medical Research and Dept of Clinical Neurosciences,

University of Cambridge, Wellcome Trust /MRC Building, Addenbrookes Hospital,

Hills Road, Cambridge CB2 0XY, UK, [email protected]

Suzuki Toshiharu

Hokkaido University, Sapporo, Japan

Thies E.

Max-Planck-Unit for Structural Molecular Biology, c/o DESY, Notkestrasse 85,

22607 Hamburg, Germany

Wang Dan

Department of Psychiatry and Biobehavioral Sciences, Brain Research Institute,

UCLA, BSRB 390B, 615 Charles E. Young Dr. S., Los Angeles CA 90095-1737,

USA

Willnow Thomas

Max-Delbrueck-Center for Molecular Medicine, Robert-Roessle-Str. 10, D-13125

Berlin, Germany, [email protected]

Wu Chengbiao

Stanford University School of Medicine, Dept of Neurology, CA 94305,

Stanford, USA