Attenuation of Rhes activity significantly delays the appearance of behavioral symptoms in a mouse model of Huntington's disease.
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.
Applied Biopsychology Program, Department of Psychology, University of New Orleans, New Orleans, Louisiana, United States of America.
Brandon A
BA
Baiamonte
Franklin A
FA
Lee
Steve T
ST
Brewer
Daniela
D
Spano
Gerald J
GJ
LaHoste
D000818:Animals; D001522:Behavior, Animal; D001835:Body Weight / Q000235:genetics; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004421:Dystonia / Q000150:complications; D005260:Female; D019204:GTP-Binding Proteins / Q000172:deficiency* / Q000235:genetics*; D055786:Gene Knockout Techniques; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000150:complications / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D019204:GTP-Binding Proteins; C488189:Rasd2 protein, mouse