Dayton Hunn

Introduction: Huntington’s Disease (HD) is an autosomal dominant inherited disease in the huntingtin gene characterized by choreiform movement, severe cognitive decline, and behavioral changes, marked by death within 15 years of symptom presentation[1]. Although this disease was first described in the late 19^th century, both a cure and disease-altering treatments remain elusive. Furthermore, the precise cellular mechanism of neuronal death in the caudate and putamen, the hallmark of HD, seems just out of reach despite a prevalence of about 6 in 100,000 in the United States[2]. Genetically, HD is diagnosed by a repeat expansion in the Huntintin gene (Htt), with disease severity correlating to expansion size. In early animal models, it was noted that programmed defects in calcium signaling conferred an HD phenotype, suggesting a relationship between HD and calcium regulation[3],[4],[5]. Recent studies have evaluated the interactions of both htt and mutant huntintin (mHtt)[6], as well as mhtt’s role in intracellular transport[7], endoplasmic reticulum (ER) dysfunction[8], mitochondria/ER axis control[9], and peripheral effects of mHtt[10]. Methods: Tandem affinity purification was used to evaluate the interaction od mHtt and Htt, fluorescence and confocal microscopy, was used to investigate Htt’s role in intracellular transport, immunostaining was used to visualize ER and mitochondrial involvement, and patch-clamp was used to determine the effects of skeletal muscle. Results: mHtt was found to preferentially associate and active proteins involved with mitochondrial dysfunction, and RNA post-translational modification and transport. Pathologic increases in intracellular mHTT was found to interact at each step of the protein secretory pathway. These increases in mHTT also conferred ER dysfunction, activating apoptosis pathways. Lastly, mHtt was found to alter the physiological dynamics of skeletal muscle contraction in the periphery. Conclusion: Various studies^7-11 have illustrated the role of mHtt and problems in calcium handling resulting in cell death, which is a hallmark of HD. Calcium modification and buffering systems could offer a novel approach to treating the symptoms or preventing the progression of HD in future populations.

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