@article {Coffey096990, author = {Sydney R. Coffey and Robert M. Bragg and Shawn Minnig and Seth A. Ament and Anne Glickenhaus and Daniel Shelnut and Jos{\'e} M. Carrillo and Dominic D. Shuttleworth and Julie-Anne Rodier and Kimihiro Noguchi and C. Frank Bennett and Nathan D. Price and Holly B. Kordasiewicz and Jeffrey B. Carroll}, title = {Peripheral Htt silencing does not ameliorate central signs of disease in the B6.HttQ111/+ mouse model of Huntington{\textquoteright}s Disease}, elocation-id = {096990}, year = {2016}, doi = {10.1101/096990}, publisher = {Cold Spring Harbor Laboratory}, abstract = {Huntington{\textquoteright}s disease (HD) is an autosomal dominant neurodegenerative disease whose neuropathological signature is a selective loss of medium spiny neurons in the striatum. Despite this selective neuropathology, the mutant protein (huntingtin) is found in virtually every cell so far studied, and, consequently, phenotypes are observed in a wide range of organ systems both inside and outside the central nervous system. We, and others, have suggested that peripheral dysfunction could contribute to the rate of progression of striatal phenotypes of HD. To test this hypothesis, we lowered levels of huntingtin by treating mice with antisense oligonucleotides (ASOs) targeting the murine Huntingtin gene. To study the relationship between peripheral huntingtin levels and striatal HD phenotypes, we utilized a knock-in model of the human HD mutation (the B6.HttQ111/+ mouse).We treated mice with ASOs from 2-10 months of age, a time period over which significant HD-relevant signs progressively develop in the brains of HttQ111+ mice. Peripheral treatment with ASOs led to persistent reduction of huntingtin protein in peripheral organs, including liver, brown and white adipose tissues. This reduction was not associated with alterations in the severity of HD-relevant signs in the striatum of HttQ111/+ mice at the end of the study, including transcriptional dysregulation, the accumulation of neuronal intranuclear inclusions, and behavioral changes such as subtle hypoactivity and reduced exploratory drive. These results suggest that the amount of peripheral reduction achieved in the current study does not significantly impact the progression of HD-relevant signs in the central nervous system.}, URL = {https://www.biorxiv.org/content/early/2016/12/29/096990}, eprint = {https://www.biorxiv.org/content/early/2016/12/29/096990.full.pdf}, journal = {bioRxiv} }