IN VIVO PROTEOMICS OF THE HUNTINGTIN PROTEIN

Huntington's disease is caused by loss of neurons in the cortex of the brain due to a mutation in the gene that codes for the Huntingtin protein. The mutations found in Huntingtin are dominant (i.e. a mutant gene causes disease in the presence of a normal gene) and consist of an increase in a part of the protein that codes for a repeat of the amino acid glutamine. When more than 35 consequtive glutamines are present, the function of Huntingtin is altered and disease occurs. In order to determine how the increase in glutamines alters the function of Huntingtin, we will construct genetically altered mice, in which the Huntingtin protein, either the normal or the mutant form, has been equipped with a tag that allows it, and any proteins with which it is associated in the cell, to be extracted and purified. The identity of the Huntingtin associated proteins can then be determined by a sensitive technique that measures protein mass. In this way we hope to identify those cellular proteins that are affected by the mutation in the Huntingtin protein in order to cause Huntington's disease.