Gene expression changes in corticostriatal neurons of Huntington's Disease transgenic mice and postmortem human brains

Abstract

Transcriptional dysregulation occurs in Huntington's Disease (HD). It affects striatal vulnerable neurons and neurons that are resistant against neurodegeneration (Zucker et al. 2005). The most affected brain region in HD besides the striatum is the cortex. Searching for causes that explain the selective neurodegeneration, we studied deep layer cortical neurons projecting to the striatum, which we isolated by Laser Capture Microdissection from sections of R6/2 transgenic mice and postmortem human HD brain. We have examined in detail both the mRNAs showing enrichment in the deep layer cortical cells and mRNAs showing most dramatic differential expression in the disease model. Cortical neurons from motor cortex (M1 and M2) of HD transgenic mice demonstrate significant changes in gene expression: 329 decreases and 94 increases in Affymetrix microarrays, 39000 mRNA probesets. Compared to cortical homogenate studies, several new mRNAs are detected in the microdissected deep layer cortical neurons. Comparing the detected murine changes to those in human postmortem HD brain by real-time PCR shows that some gene expression changes also occur in human HD tissue in the primary motor cortex (Brodmann Area 4) but not in the prefrontal association cortex (Brodmann Area 9). In deep layers of both R6/2 mice and postmortem HD human cortex, the expression of lin7b is significantly decreased. Lin7b is a structural polarity molecule implicated in protein sorting, intracellular transport, dendritic outgrowth and synaptic plasticity. We therefore postulate that corticostriatal neurons may be affected in HD by disturbance of polarity.