Abstract
Many trinucleotide repeat disorders exhibit region-specific toxicity within tissues, the basis of which cannot be explained by traditional methods. For example, in Huntington's Disease (HD), the toxic disease-causing protein is ubiquitously expressed. However, only the medium spiny neurons in the striatum are initially targeted for death. Many changes are likely to initiate in these cells at an intracellular and microstructural level long before there is a measureable phenotype, but why some regions of the brain are more susceptible to death is unknown. This chapter describes a method to detect functional changes among brain regions and cell types, and link them directly with region-specific physiology. Due to the neurodegeneration that accompanies many triplet repeat disorders, we focus on the brain, although the methods described in this chapter can be translated to other tissue types. We integrate immunohistology and traditional mass spectrometry with a novel mass spectrometry imaging technique, called nanostructure initiated mass spectrometry (NIMS). When used together, these tools offer unique insights into region-specific physiology of the brain, and a basis for understanding the region-specific toxicity associated with triplet repeat disorders.