Abstract
Huntington's disease (HD) is a neuropsychiatric disorder characterized by choreiform movement of the limbs, cognitive disability, psychosis and dementia. It is invariably associated with an abnormally long CAG expansion within the IT15 gene on human chromosome 4. Although the mutant huntingtin protein is ubiquitously expressed in HD patients, cellular degeneration occurs predominantly in neurons within the corpus striatum and cerebral cortex. The Ras homolog Rhes is expressed very selectively in the precise brain areas affected by HD. Recent in vitro work suggests that Rhes may be a co-factor with mutant huntingtin in cell death. The objective of the present study was to examine whether the inhibition of Rhes would attenuate or delay the symptoms of HD in vivo. We used a transgenic mouse model of HD crossed with Rhes knockout mice to show that the behavioral symptoms of HD are regulated by Rhes. HD+/Rhes−/− mice showed significantly delayed expression of HD-like symptoms in this in vivo model. Drugs that block or inhibit the actions of Rhes may be useful as the first treatments for HD.
Highlights
Huntington’s disease (HD) is a complex, progressive neurodegenerative disorder that results in deficits of motor function, cognition, and mood [1]
HD is caused by a genetic defect that is characterized by an unstable expansion of a trinucleotide repeat (CAG, which codes for glutamine) within the IT15 gene on human chromosome 4 [2]
We used the R6/1 line which contains,115 CAG repeats and shows symptoms that develop in mid-life that are homologous to the motor symptoms of HD
Summary
Huntington’s disease (HD) is a complex, progressive neurodegenerative disorder that results in deficits of motor function, cognition, and mood [1]. HD is caused by a genetic defect that is characterized by an unstable expansion of a trinucleotide repeat (CAG, which codes for glutamine) within the IT15 gene on human chromosome 4 [2]. The mutant gene (mHtt) is transmitted in an autosomal dominant matter, such that, on average, 50% of the offspring of an affected heterozygous individual will have HD. The long stretch of glutamine amino acids present in the mHtt protein (huntingtin) is believed to cause neurodegeneration and the symptoms that constitute HD [4,5,6,7,8]
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