HUNTINGTON’S DISEASE – CORE CONCEPTS AND CURRENT ADVANCES Edited by Nagehan Ersoy Tunali Huntington’s Disease – Core Concepts and Current Advances Edited by Nagehan Ersoy Tunali Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2012 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work Any republication, referencing or personal use of the work must explicitly identify the original source As for readers, this license allows users to download, copy and build upon published chapters even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications Notice Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher No responsibility is accepted for the accuracy of information contained in the published chapters The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book Publishing Process Manager Gorana Scerbe Technical Editor Teodora Smiljanic Cover Designer InTech Design Team First published February, 2012 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from orders@intechweb.org Huntington’s Disease – Core Concepts and Current Advances, Edited by Nagehan Ersoy Tunali p cm ISBN 978-953-307-953-0 Contents Preface IX Part Cell Biology and Modeling of Huntington's Disease Chapter Huntington’s Disease: From the Physiological Function of Huntingtin to the Disease Laurence Borgs, Juliette D Godin, Brigitte Malgrange and Laurent Nguyen Chapter Modeling Huntington’s Disease: in vivo, in vitro, in silico 43 Nagehan Ersoy Tunalı Chapter Molecular Mechanism of Huntington’s Disease — A Computational Perspective Giulia Rossetti and Alessandra Magistrato Part 67 Neuropathological Mechanisms and Biomarkers in Huntington's Disease 99 Chapter Biomarkers for Huntington’s Disease 101 Jan Kobal, Luca Lovrečič and Borut Peterlin Chapter Quinolinate Accumulation in the Brains of the Quinolinate Phosphoribosyltransferase (QPRT) Knockout Mice 121 Shin-Ichi Fukuoka, Rei Kawashima, Rei Asuma, Katsumi Shibata and Tsutomu Fukuwatari Chapter Alterations in Expression and Function of Phosphodiesterases in Huntington’s Disease Robert Laprairie, Greg Hosier, Matthew Hogel and Eileen M Denovan-Wright 133 VI Contents Part Cognitive Dysfunction in Huntington's Disease 173 Chapter Cognition in Huntington's Disease 175 Tarja-Brita Robins Wahlin and Gerard J Byrne Chapter Early Dysfunction of Neural Transmission and Cognitive Processing in Huntington’s Disease 201 Michael I Sandstrom, Sally Steffes-Lovdahl, Naveen Jayaprakash, Antigone Wolfram-Aduan and Gary L Dunbar Chapter Endogenous Attention in Normal Elderly, Presymptomatic Huntington’s Disease and Huntington’s Disease Subjects 232 Charles-Siegfried Peretti, Charles Peretti, Virginie-Anne Chouinard and Guy Chouinard Chapter 10 Part Computational Investigations of Cognitive Impairment in Huntington's Disease Eddy J Davelaar 243 Transcriptional and Post-Transcriptional Dysregulation in Huntington's Disease 267 Chapter 11 Targeting Transcriptional Dysregulation in Huntington’s Disease: Description of Therapeutic Approaches 269 Manuela Basso Chapter 12 ZNF395 (HDBP2 /PBF) is a Target Gene of Hif-1α 287 Darko Jordanovski, Christine Herwartz and Gertrud Steger Chapter 13 Role of Huntington’s Disease Protein in Post-Transcriptional Gene Regulatory Pathways Brady P Culver and Naoko Tanese Part Metabolic Dysregulation in Huntington's Disease 295 321 Chapter 14 Energy Metabolism in Huntington’s Disease Fabíola M Ribeiro, Tomas Dobransky, Eduardo A D Gervásio-Carvalho, Jader S Cruz and Fernando A Oliveira 323 Chapter 15 The Use of the Mitochondrial Toxin 3-NP to Uncover Cellular Dysfunction in Huntington’s Disease 347 Elizabeth Hernández-Echeagaray, Gabriela De la Rosa-López and Ernesto Mendoza-Duarte Contents Chapter 16 Consequences of Mitochondrial Dysfunction in Huntington's Disease and Protection via Phosphorylation Pathways 361 Teresa Cunha-Oliveira, Ildete Luísa Ferreira and A Cristina Rego Chapter 17 Cholesterol Metabolism in Huntington’s Disease Valerio Leoni, Claudio Caccia and Ingemar Björkhem Part 391 Therapeutic Targets in Huntington's Disease 413 Chapter 18 Cellular Therapies for Huntington’s Disease C M Kelly and A E Rosser Chapter 19 Ameliorating Huntington's Disease by Targeting Huntingtin mRNA 441 Melvin M Evers, Rinkse Vlamings, Yasin Temel and Willeke M C van Roon-Mom Chapter 20 Don’t Take Away My P: Phosphatases as Therapeutic Targets in Huntington’s Disease 465 Ana Saavedra, Jordi Alberch and Esther Pérez-Navarro Chapter 21 BDNF in Huntington’s Disease: Role in Pathogenesis and Treatment 495 Maryna Baydyuk and Baoji Xu Part Learning to Live with Huntington's Disease 415 507 Chapter 22 Risk and Resilience: Living with a Neurological Condition with a Focus on Health Care Communications 509 Kerstin Roger and Leslie Penner Chapter 23 Communication Between Huntington’s Disease Patients, Their Support Persons and the Dental Hygienist Using Talking Mats 531 Ulrika Ferm, Pernilla Eckerholm Wallfur, Elina Gelfgren and Lena Hartelius VII Preface In the late 20th century the scientific community has witnessed a glorious outcome of an enviable long term collaboration among researchers working on Huntington’s Disease The invaluable efforts of the 58 international scientists and clinicians were eventuated in successful mapping of the disease gene to chromosome in 1983 Being the first hereditary disease for which a DNA marker was used to localize the disease gene, HD has served as a model for mapping other genetic diseases This achievement not only demonstrated the power of using linkage to DNA polymorphisms to approach genetic diseases, but also contributed to the concept of Human Genome Project Ten years later the gene was isolated and the genetic mutation causing HD was identified as the expansion in the number of CAG repeats in the first exon of the gene Since that time, extensive research has been going on to decipher the changes in the molecular mechanisms caused by polyglutamines in the mutant protein product Although there is only one gene and one mutation causing the disease, genotypephenotype correlations and the molecular pathways involved were turned out to be extremely complex One of the main complexities is that there is a huge amount of variation in the age of onset and the severity of symptoms among HD patients of the same CAG repeat size, which implicates the existence of genetic modifiers of the disease The other is that, both gain of toxic function and loss of wild type function of the huntingtin protein are involved at the molecular level In the last almost 20 years many considerable achievements have been made and many questions found persuasive answers, however, we are still left with many missing pieces of the HD puzzle There are currently no drugs available to cure the disease, which implies that we still have some way to go before completely understanding the neurodegenerative process in HD In this regard, sharing of the experiences, the data, and the knowledge is of great importance to both the HD families and the scientific world This book, “Huntington’s Disease - Core Concepts and Current Advances”, was prepared to serve as a source of up-to-date information on a wide range of issues involved in Huntington’s Disease I believe that it will help the clinicians, health care providers, researchers, graduate students and life science readers to increase their X Preface understanding of the clinical correlates, genetic aspects, neuropathological findings, cellular and molecular events and potential therapeutic interventions involved in HD The book not only serves reviewed fundamental information on the disease but also presents original research in several disciplines, which collectively provide comprehensive description of the key issues in the area Nagehan Ersoy Tunalı, PhD Halic University, Faculty of Arts and Sciences, Department of Molecular Biology and Genetics, Istanbul, Turkey 540 Huntington’s Disease — Core Concepts and Current Advances The two researchers were trained in EFFC by evaluating video-recordings of conversations involving persons with HD that were not used in the study Thereafter, the films of the 22 conversations were evaluated in a randomized order First, the two researchers rated each recording independently This meant that they looked at the recording together but did their own rating Subsequently, the researchers discussed their ratings and reached a consensus score for each factor in each recording The maximum score for each conversation was 16 Twelve points is the cut-off for an acceptable level of effectiveness (Murphy et al., 2010a) To check for interrater reliability, two independent external raters evaluated 30 % of the data using the same procedure To check for intra-rater reliability, the two main researchers did a second evaluation of 30 % of the data a week after the first evaluation The two conditions were also compared with respect to time and with respect to number of questions and follow-up questions that were asked The answers to the questionnaire items were transferred to a descriptive scale as follows: all/always (4), most/usually (3), a few/occasionally (2), and none/never (1) The individual scores for the six questions were added to form a total involvement score for each condition and participant Means were calculated as well Written comments in questionnaires were analysed and categorised with regard to content Statistical calculations were done using SPSS (version 19) Internal interrater reliability, measured using intra-class correlation (ICC) was 0.85 External interrater reliability, between the main two researchers and the external raters, was 0.64 The reliability between the researchers was higher (0.91) for the nonTM condition than for the TM condition (0.78) Intrarater reliability calculated on the basis of the researchers’ consensus scores was 0.96 Differences in scores of communicative effectiveness and involvement as well as differences in the duration of the two conditions were analysed using Wilcoxon Signed Ranks Test (p