Abstract Details

Title A BAC Transgenic Mouse Model of Spinocerebellar Ataxia Type 31 (SCA31) Manifests Late-Onset Motor Dysfunction and RNA Foci in Purkinje Cells

Topic Movement Disorders

Presentation(s) S43 - (-)

Poster/Presentation
Number 007

Objective

Background SCA31 is caused by the presence of complex penta-nucleotide repeats containing (TGGAA)n, (TAGAA)n and (TAAAA)n in an intronic region shared by two genes, BEAN1 (brain expressed, associated with NEDD4, 1) and TK2 (thymidine kinase 2). The length of this mutation is inversely correlated with the age at onset. As some control populations also harbor similar complex repeats containing (TAGAA)n and (TAAAA)n, (TGGAA)n is considered to be essential for SCA31 pathogenesis. In human SCA31 brains, Purkinje cells are primarily affected showing characteristic degenerative changes. Furthermore, abnormal RNA structures called RNA foci are occasionally detected in Purkinje cell nuclei by fluorescent in situ hybridization (FISH) using probes against the (UGGAA)n-containing transcripts.

Design/Methods To dissect the molecular mechanisms underlying SCA31, a transgenic mouse model was generated by injecting DNA fragments from a BAC clone, Ca0256P13, derived from an SCA31 patient homozygous for the mutation. This BAC clone encompasses the entire genomic region of BEAN1 including the SCA31 mutation.

Results Four lines of BAC transgenic mice of SCA31 were generated and maintained. We confirmed that these mice express human BEAN1 in the brain, including the cerebellum, at least at the RNA level. Rotarod test showed impaired motor performances starting at approximately 12 months of age. Although conventional histopathologic examinations revealed no obvious changes in the cerebellum at 18 months of age, FISH analysis disclosed RNA foci containing (UGGAA)n in small fractions of Purkinje cells.

Conclusions We succeeded in generating the first SCA31 mouse model. The transgenic human BEAN1-overexpression mice expressed the SCA31-mutation containing gene in the brain and showed RNA foci in Purkinje cell nuclei. We are currently investigating how far these mouse models are relevant to SCA31 pathophysiology in human.

Authors/Disclosures
Nozomu Sato, MD (Dept. of neurology & Neurological Science, Tokyo Medical & Dental University) PRESENTER	No disclosure on file
Kinya Ishikawa, MD, PhD (Tokyo Med & Dental Univ)	Dr. Ishikawa has nothing to disclose.
Yusuke Niimi	No disclosure on file
Hidehiro Mizusawa, MD, PhD (National Center of Neurology and Psychiatry)	No disclosure on file
	No disclosure on file

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