Abstract
<h3>Objective:</h3> To identify molecular pathways underlying caudate, medium spiny neuron (MSN) degeneration in post-mortem Huntington’s Disease (HD) subjects. <h3>Background:</h3> Huntington’s Disease is an autosomal dominant, neurodegenerative disorder marked by aberrant expression of the expanded Huntingtin gene (HTT). Expression of mutant <i>HTT</i> results in selective atrophy of MSNs in the striatum. Previous studies have analyzed the caudate transcriptome in HD with a lack of consistency and an absence of corresponding proteome characterization. <h3>Design/Methods:</h3> Our study includes 20 HD and 20 neurotypical control post-mortem human subjects that are 55% female with a mean age of 57.6 at the time of death. We employed laser capture microdissection (LCM) to isolate the whole cell bodies of MSNs (~5000 neuron enrichments) from each of the 40 samples, facilitating single-cell analysis of the cytosol in addition to MSN nuclei. We performed RNA sequencing and labeled quantitative tandem mass spectrometry (TMT-MS/MS) on the same MSN lysate. Differential molecular analyses reveal RNA and protein isoform changes and phospho-site signaling changes in HD caudate. <h3>Results:</h3> We present MSN transcriptome, proteome, and phospho-proteome differences underlying HD at both the transcript and protein feature levels. Our findings suggest that there are <i>HTT</i> protein-protein interactions specific to MSN degeneration in HD. <h3>Conclusions:</h3> Applying this methodology and analytical paradigm, we expect to find (i) differentially expressed pathways (transcript and protein isoforms) underlying HD in MSN populations (ii) MSN-specific gene and protein interaction networks that have previously not been defined in controls or HD subjects, and (iii) phosphorylation-driven signaling changes in specific protein pathways that are closer to functional gene expression underlying HD. <b>Disclosure:</b> Mr. El-Halawani has nothing to disclose. Miss Martins has nothing to disclose. Dr. A Bharadwaj has nothing to disclose. Dr. Tao has nothing to disclose. The institution of Dr. Chen has received research support from National Science Foundation. Dr. Kleinman has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Dr. Kleinman has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Austin Sidley law Firm. Daniel Weinberger has nothing to disclose. Dr. Hyde has received personal compensation for serving as an employee of Lieber Institute for Brain Development. The institution of Dr. Hyde has received research support from National Institutes of Health.
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