Abstract Details

Title Spontaneous Rat Mutant - A New Model for X-Linked Ataxia

Topic Movement Disorders

Presentation(s) P02 - (-)

Poster/Presentation
Number 084

Objective

Background BACKGROUND: The shaker rat in the Wistar Furth (WF) background exhibits a shaking ataxia, wide stance and adult-onset progressive degeneration of Purkinje cells (PCs). The trait is X-linked recessive.

Design/Methods DESIGN/METHODS: Generation of WF/Black Norwegian F1 and genetic mapping of F2 sib-sib offspring using polymorphic markers. Immunofluorescent labeling and qPCR analysis of age-dependent progression of PC degeneration.

Results RESULTS: Using genetic analysis of an F2 cross, we were able to narrow the candidate gene region to 12Mb in q37. In contrast to complete penetrance, stereotypic phenotype and a narrow window for age of onset in the WF background, the F2 hybrid phenotype was more varied and included later age of onset and likely non-penetrance of the mutation. Analysis of Calb1, Pcp2, and Grid2 steady-state RNA levels showed decreases beginning at 3 weeks with 80-90% reduction in 6 month old affected males (compared with wildtype littermates).

Conclusions CONCLUSIONS: The shaker mutation can be mapped with an F2 cross as the phenotype in a mixed background remains easily recognizable. The later disease onset in F2s and the presence of non-penetrance highlight the effects of genetic background on PC degeneration and may permit the identification of modifier alleles. Transcriptome changes precede behavioral onset by weeks and cell loss by months. Compared with mouse models of ataxia, the shaker rat may represent a useful model for in vivo recording and modification of cerebellar function.

Authors/Disclosures
Karla P. Figueroa (University of Utah) PRESENTER	Ms. Figueroa has nothing to disclose.
	No disclosure on file
Stefan M. Pulst, MD, FAAN (University of Utah)	Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for venrock. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arrowhead. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Leverna. Dr. Pulst has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for AAN. Dr. Pulst has received personal compensation in the range of $500-$4,999 for serving as an Expert Witness for Leninthal LLC. The institution of Dr. Pulst has received research support from NINDS. Dr. Pulst has received intellectual property interests from a discovery or technology relating to health care.
David M. Greer, MD, FAAN (Boston University School of Medicine)	Dr. Greer has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Thieme, Inc. Dr. Greer has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for multiple. An immediate family member of Dr. Greer has or had stock in Vertex Pharmaceuticals. The institution of Dr. Greer has received research support from NINDS. Dr. Greer has received publishing royalties from a publication relating to health care. Dr. Greer has received publishing royalties from a publication relating to health care. Dr. Greer has received publishing royalties from a publication relating to health care. Dr. Greer has a non-compensated relationship as a Treasurer-Elect with American Neurological Association that is relevant to AAN interests or activities. Dr. Greer has a non-compensated relationship as a President with Neurocritical Care Society that is relevant to AAN interests or activities.

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