The HD mutation causes progressive lethal neurological disease in mice expressing reduced levels of huntingtin

Huntingtin is an essential protein that with mutant polyglutamine tracts in itiates dominant striatal neurodegeneration in Huntington's disease (HD). T o assess the consequences of mutant protein when huntingtin is limiting, we have studied three lines of compound heterozygous mice in which both copie s of the HD gene homolog (Hdh) were altered, resulting in greatly reduced l evels of huntingtin with a normal human polyglutamine length (Q20) and/or a n expanded disease-associated segment (Q111): Hdh(neoQ20)/Hdh(neoQ20),Hdh(n eoQ20)/Hdh(null) and Hdh(neoQ20)/Hdh(neoQ111). All surviving mice in each o f the three lines were small from birth, and had variable movement abnormal ities. Magnetic resonance micro-imaging and histological evaluation showed enlarged ventricles in similar to 50% of the Hdh(neoQ20)/Hdh(neoQ111) and H dh(neoQ20)/Hdh(null) mice, revealing a developmental defect that does not w orsen with age. Only Hdh(neoQ20)/Hdh(neoQ111) mice exhibited a rapidly prog ressive movement disorder that, in the absence of striatal pathology, begin s with hind-limb clasping during tail suspension and tail stiffness during walking by 3-4 months of age, and then progresses to paralysis of the limbs and tail, hypokinesis and premature death, usually by 12 months of age. Th us, dramatically reduced huntingtin levels fail to support normal developme nt in mice, resulting in reduced body size, movement abnormalities and a va riable increase in ventricle volume. On this sensitized background, mutant huntingtin causes a rapid neurological disease, distinct from the HD-pathog enic process. These results raise the possibility that therapeutic eliminat ion of huntingtin in HD patients could lead to unintended neurological, as well as developmental side-effects.