**Meet the editor**

Born in 1957, Dr. José Gazulla performed his medical studies at the University of Navarra, and received training in Neurology at the Hospital Universitario Marqués de Valdecilla, in Santander (Spain). He worked at the Hospital General de Teruel and Hospital San Jorge, in Huesca, before joining the Service of Neurology of Hospital Universitario Miguel Servet, in Zaragoza (Spain). His deployment as a general neurologist has not impaired his interest in the degenerative diseases of the nervous system, especially of the cerebellum, spinal cord and peripheral nerves. Deeply interested in neurological semiology and pathophysiology, as well as in genetics, imaging and molecular biology of central and peripheral nervous system disorders, his interest in the field of degenerative ataxias became evident from early in his professional career. As a result of this, a number of reports concerning the clinical manifestations, imaging, neurochemistry and pharmacological treatment of the degenerative ataxias have been published, in collaboration with a small number of close collaborators.

Contents

**Preface VII** 

Chapter 1 **Model Systems for Spinocerebellar Ataxias:** 

Chapter 5 **Spinocerebellar Ataxia Type 2 77** 

Chapter 6 **Machado-Joseph Disease /** 

**Lessons Learned About the Pathogenesis 1**  Thorsten Schmidt, Jana Schmidt and Jeannette Hübener

Chapter 2 **Non-Mendelian Genetic Aspects in Spinocerebellar Ataxias** 

Chapter 3 **Spinocerebellar Ataxia with Axonal Neuropathy (SCAN1):** 

Chapter 4 **Eye Movement Abnormalities in Spinocerebellar Ataxias 59**  Roberto Rodríguez-Labrada and Luis Velázquez-Pérez

> Luis Velázquez-Pérez, Roberto Rodríguez-Labrada, Hans-Joachim Freund and Georg Auburger

**Clinical Features and Pathogenetic Mechanisms 139**  Ronald A. Merrill, Andrew M. Slupe and Stefan Strack

José Gazulla, Cristina Andrea Hermoso-Contreras and María Tintoré

**of Charlevoix-Saguenay (ARSACS): Clinical, Radiological and Epidemiological Aspects 155** 

Haruo Shimazaki and Yoshihisa Takiyama

Chapter 9 **Neurochemistry and Neuropharmacology of the Cerebellar Ataxias 173** 

**Spinocerebellar Ataxia Type 3 103**  Clévio Nóbrega and Luís Pereira de Almeida

Chapter 7 **Spinocerebellar Ataxia Type 12 (SCA 12):** 

Chapter 8 **Autosomal Recessive Spastic Ataxia** 

**(SCAS): The Case of Machado-Joseph Disease (MJD) 27**  Manuela Lima, Jácome Bruges-Armas and Conceição Bettencourt

**A Disorder of Nuclear and Mitochondrial DNA Repair 41**  Hok Khim Fam, Miraj K. Chowdhury and Cornelius F. Boerkoel

### Contents

#### **Preface XI**


Preface

by Dr. Rodríguez‐Labrada.

The purpose of this book has been to depict as many biochemical, genetic and molecular advances as possible, in the vast field of the spinocerebellar ataxias. In addition, potential lines of pharmacological treatment in spinocerebellar ataxia type 3, enumerated by Professor Luis Pereira, are complemented by a chapter in which the pharmacological trials of the cerebellar ataxias have been reviewed in depth. Clinical manifestations of the spinocerebellar ataxias are also included in the text, like the description by Dr. Luis Velázquez‐Pérez of those in spinocerebellar ataxia type 2, and the exhaustive review about eye movement abnormalities in cerebellar disease, written

> **Dr. Jose Gazulla** Service of Neurology,

> > Zaragoza, Spain

Hospital Universitario Miguel Servet,

### Preface

The purpose of this book has been to depict as many biochemical, genetic and molecular advances as possible, in the vast field of the spinocerebellar ataxias. In addition, potential lines of pharmacological treatment in spinocerebellar ataxia type 3, enumerated by Professor Luis Pereira, are complemented by a chapter in which the pharmacological trials of the cerebellar ataxias have been reviewed in depth. Clinical manifestations of the spinocerebellar ataxias are also included in the text, like the description by Dr. Luis Velázquez‐Pérez of those in spinocerebellar ataxia type 2, and the exhaustive review about eye movement abnormalities in cerebellar disease, written by Dr. Rodríguez‐Labrada.

> **Dr. Jose Gazulla** Service of Neurology, Hospital Universitario Miguel Servet, Zaragoza, Spain

**1** 

*Germany* 

**Model Systems for Spinocerebellar Ataxias:** 

Model systems are important tools for the investigation of pathogenic processes. Especially for diseases with a late onset of symptoms and slow progression, like most spinocerebellar ataxias (SCA), it is time-consuming or even impossible to analyze all aspects of the pathogenesis in humans. Due to the reduced lifespan of model organisms, it is possible to study disease progression in full within a reasonable timeframe and due to the shorter generation time of most model organisms more individuals can be generated and analyzed, thereby strengthening the reliability of data via an increased number of replicates. Detailed studies of the histopathology can only be performed as endpoint analyses in humans, but with the help of an animal model, multiple time points can be analyzed throughout the course of the disease. In addition, model systems allow not only for the reduction of time from idea to results but also reduce the complexity due to their smaller genome sizes, less

Before using a specific species to model a disease it is of interest to check whether the proteins affected in humans are conserved within the respective model organism in order to increase the probability that binding partners and other keyplayers, involved in the pathogenesis of this disease, are likewise conserved. For those SCA which are caused by polyglutamine (polyQ) expansions, the respective affected genes are conserved in most organisms used as models (Table 1). Especially the proteins affected in SCA2, SCA6 and SCA17 are conserved with high similarity down to even yeast. This is not surprising as the TATA-binding protein (affected in SCA17) or a subunit of a voltage-dependent calcium channel (affected in SCA6) are important proteins for cellular maintenance. Although polyQ repeats are comparatively frequent in drosophila (Alba et al., 2007), only the repeat region of the TATA-binding protein is conserved. For most other non-mammalian model organisms, the respective orthologues are smaller and the polyQ repeats itself or even including the whole surrounding domains are not conserved. For analyses of SCA, various model systems have been employed. From the worm (*Caenorhabditis elegans*) and the fly (*Drosophila melanogaster*) all the way to mammals, i.e. the mouse (*Mus musculus*), model systems have
