RT Journal Article
SR Electronic
T1 Peripheral Htt silencing does not ameliorate central signs of disease in the B6. HttQ111/+ mouse model of Huntington’s Disease
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 096990
DO 10.1101/096990
A1 Sydney R. Coffey
A1 Robert M. Bragg
A1 Minnig Shawn
A1 Seth A. Ament
A1 Glickenhaus Anne
A1 Shelnut Daniel
A1 José M. Carrillo
A1 Dominic D. Shuttleworth
A1 Rodier Julie-Anne
A1 Noguchi Kimihiro
A1 C. Frank Bennett
A1 Nathan D. Price
A1 Holly B. Kordasiewicz
A1 Jeffrey B. Carroll
YR 2017
UL http://biorxiv.org/content/early/2017/01/27/096990.abstract
AB Huntington’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.