**Model Systems for Spinocerebellar Ataxias: Lessons Learned About the Pathogenesis**

Thorsten Schmidt\*#, Jana Schmidt\* and Jeannette Hübener\* *Eberhard-Karls-University Tuebingen, Medical Genetics Germany* 

#### **1. Introduction**

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 genes, nonredundant pathways, and a simpler nervous system.

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
