Journal Article

Neuronal targets for reducing mutant huntingtin expression to ameliorate disease in a mouse model of Huntington's disease

Li, Yuqing, Wang, Nan, Shirasaki, Dyna, Lu, Xiao-Hong, Gu, Xiaofeng, Holley, Sandra M, Yang, X William, Gray, Michelle, Cepeda, Carlos, Levine, Michael S, Cantle, Jeffrey P, Dong, Hongwei, Greiner, Erin

2014

Overview

A potential treatment for Huntington's disease involves reducing expression of the mutant gene, but it is unclear to which part of the brain the treatment should be directed. Now, X. William Yang and colleagues show that reducing HTT expression in both the striatum and the cortex provides the most benefit for ameliorating disease in mice when compared with reducing expression in just one of the two brain structures. Huntington's disease (HD) is a fatal dominantly inherited neurodegenerative disorder caused by a CAG repeat expansion leading to an elongated polyglutamine stretch in huntingtin 1 . Mutant huntingtin (mHTT) is ubiquitously expressed in all cells but elicits selective cortical and striatal neurodegeneration in HD 2 . The mechanistic basis for such selective neuronal vulnerability remains unclear. A necessary step toward resolving this enigma is to define the cell types in which mHTT expression is causally linked to the disease pathogenesis. Using a conditional transgenic mouse model of HD, in which the mice express full-length human mHTT from a bacterial artificial chromosome transgene (BACHD) 3 , we genetically reduced mHTT expression in neuronal populations in the striatum, cortex or both. We show that reduction of cortical mHTT expression in BACHD mice partially improves motor and psychiatric-like behavioral deficits but does not improve neurodegeneration, whereas reduction of mHTT expression in both neuronal populations consistently ameliorates all behavioral deficits and selective brain atrophy in this HD model. Furthermore, whereas reduction of mHTT expression in cortical or striatal neurons partially ameliorates corticostriatal synaptic deficits, further restoration of striatal synaptic function can be achieved by reduction of mHTT expression in both neuronal cell types. Our study demonstrates distinct but interacting roles of cortical and striatal mHTT in HD pathogenesis and suggests that optimal HD therapeutics may require targeting mHTT in both cortical and striatal neurons.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/51 / 42 / 42/41 / 631/378/1689/1558 / 64/60 / Analysis / Animals / Behavioral Symptoms - genetics / Behavioral Symptoms - pathology / Biomedicine / Cancer Research / Corpus Striatum - metabolism / Corpus Striatum - pathology / Disease Models, Animal / Gene Expression Regulation / Gene mutations / Genetic aspects / Genetic disorders / Genetic Therapy / Genotype & phenotype / Humans / Huntingtin Protein / Huntington Disease - genetics / Huntington Disease - metabolism / Huntington Disease - pathology / Huntington Disease - therapy / Huntington's chorea / Infectious Diseases / letter / Metabolic Diseases / Mice / Molecular Medicine / Motor Activity - genetics / Mutation / Nerve Tissue Proteins - biosynthesis / Nerve Tissue Proteins - genetics / Neurological disorders / Neurons - metabolism / Neurons - pathology / Neurosciences / Rodents