Cerebellar allografts survive and transiently alleviate ataxia in a transgenic model of spinocerebellar ataxia type-1

Spinocerebellar ataxia type 1 (SCA-1) is one of several neurodegenerative d iseases, including Huntington's disease, spinobulbar muscular atrophy, dent atorubral-pallidoluysian atrophy, and SCA-S, SCA-3, SCA-6, and SCA-7, each caused by an expanded number of CAG repeats in the coding region of their r espective genes. The mechanism by which the resulting proteins are pathogen ic is unknown. Clinical trials of neural transplants in Huntington's diseas e patients are under way. While initial reports are encouraging definitive evidence of graft survival in patients despite the ongoing disease process is not possible with current imaging techniques. Transplants in primates ha ve shown long-term survival of striatal grafts and recovery of function, bu t have used lesioning to model Huntington's phenotypically. Studies of stri atal grafts in a transgenic mouse model of Huntington's have not yet shown a behavioral benefit. We describe a behavioral benefit of cerebellar grafts in a transgenic model of SCA-1 in which the ataxic phenotype results from expression of an expanded ataxin-1 protein. Mice were transplanted at an ag e when their ataxic phenotype is just becoming evident. Compared with sham- operated littermates, grafted mice showed better performance on multiple be havioral tests of cerebellar function. Differences persisted for 10 to 12 w eeks posttransplant, after which there was a progressive decline in motor p erformance. At 20 weeks postsurgery, donor Purkinje cell survival was evide nt in 9 of 12 graft recipients. These results indicate that transplants can have behavioral benefits and grafts can survive longterm despite the ongoi ng pathological process in a brain actively expressing an expanded polyglut amine protein. (C) 1999 Academic Press.