Research Grant Award

Sue M Travis, PhD

University of Iowa
Effects of Polyglutamine Expansion on Activity of Ataxin-3, the Spinocerebellar Ataxia 3 Disease Protein

Prof. Dr. Med. U. Wullner, MD, PhD

University Bonn
Phosphorylation of Ataxin3-implication for cellular localization and viability

The degenerative ataxias comprise a number of heterogeneous diseases, many of which are genetically determined. The identification of CAG trinucleotide repeats in coding regions of the DNA in autosomal dominant spinocerebellar ataxia (SCA) 1,2,3,6 and 7 marked the beginning of a new area in ataxia research. CAG codes for the amino acid glutamine, thus these disorders are also called polyglutamine disorders and research has focused on the effects of expanded glutamine stretches in the encoded proteins, which tend to aggregate in the cell, especially in the nerve cell's nucleus where so called neuronal intranuclear inclusions are found in specific brain regions. The same type of mutation in different genes, coding for different proteins, underlies several distinct diseases, thus not only the expanded glutamine stretches but also the individual gene and the function of the affected protein are important determinants of the disease. In a cell, proteins are not simply manufactured and put into usage but modified like a car according to the buyers demand. In addition, as some cars are modified by their drivers to gain more speed, proteins are modified to fulfill certain demands. A common modification is called phosphorylation, i.e. extra phosphor is added to the protein to govern intracellular trafficking, increase or decrease certain functions or in some cases determine the proteins lifetime (like a wheel clamp or a signal for a tow vehicle). In SCA1, phosphorylation has been shown to be important for the disease process. We investigate the most common ataxia in the U.S and Europe, SCA3. Nothing is known about phosphorylation in the disease protein, Ataxin3 (AT3) and whether one could work on this phosphorylation process to alleviate the disease. We thus started to analyze the phosphorylation status of AT3 and identified the particular positions in the protein which are phosphorylated. Extra phosphor could be of critical importance for nuclear localization, thus only phosphorylated AT3 protein may get into the nucleus to form intranuclear aggregates which are believed to be critical for the disease to develop. The funded study supports an additional PhD student to investigate the effect of phosphorylation on cellular transport of the expanded disease protein AT3, the occurrence of neuronal intranuclear inclusions and the lifetime of AT3.