Neuronal Profiling in Mouse Models of Huntington’s Disease

fascinating example of enhanced cell-type-specific disease vulnerability is seen in Huntington’s disease (HD), a monogenic neurodegenerative disease caused by expansion of CAG (glutamine-encoding) trinucleotide repeats in the huntingtin gene. In HD, medium-sized spiny neurons of the striatum are dramatically affected, and in late stages of this disease, most medium spiny neurons are lost. Eventually, other classes of neurons are also affected in HD, but striatal medium spiny neurons are among the earliest stricken. The enhanced vulnerability of medium spiny neurons cannot be explained merely by the pattern of huntingtin expression, as the huntingtin gene itself is expressed in many cells. Thus, medium spiny neurons may express other factors that make them especially susceptible to death in HD (or may fail to express factors that would make them more resistant). To identify such susceptibility factors, our lab is using TRAP to compare the molecular profiles of more resistant and more vulnerable cell populations in HD. The levels of factors that correlate with enhanced vulnerability will be genetically manipulated, and the impact of these changes on the phenotype of Huntington’s disease model mice will be assessed. The aim of this research is to identify protective factors that may alter the course of Huntington’s disease progression and reveal insights into medium spiny neuron physiology.