Exon 1 of the HD Gene with an Expanded CAG Repeat Is Sufficient to Cause a Progressive Neurological Phenotype in Transgenic Mice

Abstract

Huntington's disease (HD) is one of an increasing number of neurodegenerative disorders caused by a CAG/polyglutamine repeat expansion. Mice have been generated that are transgenic for the 5' end of the human HD gene carrying (CAG)115-(CAG)150 repeat expansions. In three lines, the transgene is ubiquitously expressed at both mRNA and protein level. Transgenic mice exhibit a progressive neurological phenotype that exhibits many of the features of HD, including choreiform-like movements, involuntary stereotypic movements, tremor, and epileptic seizures, as well as nonmovement disorder components. This transgenic model will greatly assist in an eventual understanding of the molecular pathology of HD and may open the way to the testing of intervention strategies.

Cellular Therapy and Induced Neuronal Replacement for Huntington's Disease

“…R6/2 mice express a 144 CAG repeat expansion within the first exon of the huntingtin gene, which yields a relatively severe disease phenotype. Untreated R6/2 mice develop rapidly progressive neurological impairment, and typically die between 13 and 15 weeks of age [140,141]. As in the rat, AdBDNF and AdNoggin treatment induced significant neuronal recruitment in both R6/2 mice and their wild-type controls [98].…”

Cortical Metabolites as Biomarkers in the R6/2 Model of Huntington's Disease

“…no. 203605) according to established protocols (Mangiarini et al, 1996). Genotyping and CAG repeat number were also determined by Laragen (Los Angeles, CA, USA).…”

“…This study had two goals: to determine (1) if neurochemical changes in cortex and striatum are detectable before brain shrinkage, currently one of the most sensitive indicators of disease and (2) if brain metabolite information could be condensed into an one or two dimensional biomarker that could be used to track disease progression. We studied the R6/2 transgenic mouse, a severe and rapid model of HD that expresses a toxic fragment of exon 1 of the human HD gene with B150 CAG repeats (Mangiarini et al, 1996). In this mouse model, abnormalities in running wheel and climbing behavior parallel the appearance of nuclear inclusions as early as 4 to 4.5 weeks (Davies et al, 1997;Hickey et al, 2005).…”

Mouse models of Huntington's disease

“…The N-terminal transgenic lines demonstrated that an N-terminal mutant HTT fragment was sufficient to elicit HD-like neurological phenotypes in the mouse. The R6/1 and R6/2 lines, which express mutant human exon 1 HTT, were the first transgenic lines produced (Mangiarini et al, 1996) and the R6/2 mouse has been the most extensively studied and utilized mouse model of HD to date. Another N-terminal transgenic mouse is the N171-82Q line (Schilling et al, 1999) expressing a 171 amino acid mutant HTT fragment under the regulation of the mouse prion promoter, which directs expression primarily in the brain.…”