TOWARD UNDERSTANDING THE MOLECULAR PATHOLOGY OF HUNTINGTONS-DISEASE

Huntington's Disease (HD) is caused by expansion of a CAG trinucleotid e beyond 35 repeats within the coding region of a novel gene, Recently , new insights into the relationship between CAG expansion in the HD g ene and pathological mechanisms have emerged, Survival analysis of a l arge cohort of affected and at-risk individuals with CAG sizes between 39 and 50 repeats have yielded probability curves of developing HD sy mptoms and dying of HD by a certain age, Animals transgenic for the fi rst exon of huntingtin with large CAG repeats lengths have been report ed to have a complex neurological phenotype that bears interesting sim ilarities and differences to HD, The repertoire of huntingtin-interact ing proteins continues to expand with the identification of HIP1, a pr otein whose yeast homologues have known functions in regulating events associated with the cytoskeleton. The ability of huntingtin to intera ct with two of its four known protein partners appears to be influence d by CAG length, Caspase 3 (apopain), a key cysteine protease known to play a seminal role in neural apoptosis, has also been demonstrated t o specifically cleave huntingtin in a CAG length-dependent manner, Man y of these features are combined in a model suggesting mechanisms by w hich the pathogenesis of HD may be initiated, The development of appro priate in vitro and animal models for HD will allow the validity of th ese models to be tested.