Spinocerebellar ataxia type 1 (SCA-1) is one of several neurodegenerative diseases, including Huntington's disease, spinobulbar muscular atrophy, dentatorubral-pallidoluysian atrophy, and SCA-2, SCA-3, SCA-6, and SCA-7, each caused by an expanded number of CAG repeats in the coding region of their respective genes. The mechanism by which the resulting proteins are pathogenic is unknown. Clinical trials of neural transplants in Huntington's disease 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 have shown long-term survival of striatal grafts and recovery of function, but have used lesioning to model Huntington's phenotypically. Studies of striatal 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 age when their ataxic phenotype is just becoming evident. Compared with sham-operated littermates, grafted mice showed better performance on multiple behavioral tests of cerebellar function. Differences persisted for 10 to 12 weeks posttransplant, after which there was a progressive decline in motor performance. At 20 weeks postsurgery, donor Purkinje cell survival was evident in 9 of 12 graft recipients. These results indicate that transplants can have behavioral benefits and grafts can survive long-term despite the ongoing pathological process in a brain actively expressing an expanded polyglutamine protein.
Bibliographical noteFunding Information:
The transgenic mice were a gift from Eric Burright and Harry Orr. The 11750V anti-ataxin-1 antibody was a gift to Harry Orr from Huda Zoghbi. The authors thank John Conrad, Mustafa Khan, and Lisa Pundt for their assistance with the surgical procedures and Nicki Nguyen, Rina Smrkovski, and Jill Marchenko for assistance in scoring the behavioral data. This investigation was supported by the National Institutes of Health under National Research Service Award 1 F31 MH11640-01A1 from the National Institute of Mental Health.
- CAG trinucleotide repeats
- Cerebellar allografts
- Neural transplants
- Polyglutamine proteins
- Spinocerebellar ataxia
- Transgenic models