Abstract for presentation at 11th International Congress of Human Genetics

Spinocerebellar ataxia type1 (SCA1), a hereditary neuronal disease, is cause by expansion of translated CAG repeat in Ataxin-1 gene. Among healthy individuals the CAG repeats vary in repeat number from 6 to 44, showing high polymorphism. In patients the numbers of the CAG repeats range from 39 to 82. Poly-glutamine tracts encoding by expanded CAG repeats are supposed to be toxic for neurons and play a crucial role for clinical deterioration. It is suggested that ATAXIN-1 functions as a chromatin-binding regulatory factor and associate with transcription in neuronal cells. Although the functional aspect of poly-glutamine tract has remained to be controversial, recent study reported that PQBP1 (poly-glutamine binding protein 1) recognizes the poly-glutamine tracts of ATAXIN-1 and is involved in the SCA1 pathology. We previously reported the repetitive region of Ataxin-1 gene in various species of primates: no repetitive structure in the region corresponding to the human CAG repeats in prosimians and New World monkeys like in rodents, perfect (uninterrupted) CAG repeats in Old World monkeys, and interrupted CAG repeats in hominoids. To gain a further insight into the molecular function of poly-glutamine tract and make clear the functional change in association with the amino-acid substitution, we performed surface plasmon resonance (SPR) assay using Biacore system. Bacterial expressed ATAXIN-1 and PQBP-1 were successfully interacted in-vitro by SPR assay. Then, we performed a further experiment to reveal a difference of interactions between PQBP1 and the no/perfect repetitive sequences. Interestingly, PQBP1 could bind the repeat in Old World monkeys (11Q), but could not the repeat in New World monkeys (6Q5P). The consequence suggests that the proline to glutamine amino acid substitutions induce the functional change in ATAXIN-1 metabolism during human evolution.