Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.HttQ111/+ mouse model of Huntington’s disease

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disease whose predominant neuropathological signature is the 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 (64% knockdown), brown adipose (66% knockdown), and white adipose tissues (71% knockdown).  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. Overall design: HttQ111/+ and Htt+/+ mice were given weekly intraperitoneal injections of Htt ASO, control ASO, or saline from 2 to 10 months of age. Striatal mRNA was sequenced from and N of 5-6 per arm (N=35 total).

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Coffey SR, Bragg RM, Minnig S, Ament SA, Cantle JP, Glickenhaus A, Shelnut D, Carrillo JM, Shuttleworth DD, Rodier JA, Noguchi K, Bennett CF, Price ND, Kordasiewicz HB, Carroll JB