Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.HttQ111- mouse model of Huntington’s diseaseReportar como inadecuado




Peripheral huntingtin silencing does not ameliorate central signs of disease in the B6.HttQ111- mouse model of Huntington’s disease - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

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.



Autor: Sydney R. Coffey, Robert M. Bragg, Shawn Minnig, Seth A. Ament, Jeffrey P. Cantle, Anne Glickenhaus, Daniel Shelnut, José M. Car

Fuente: http://plos.srce.hr/



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