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The Journal of Neuroscience, August 12, 2009, 29(32):10072-10080; doi:10.1523/JNEUROSCI.2542-09.2009

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Neurobiology of Disease
A New Transgenic Mouse Model of Gerstmann–Sträussler–Scheinker Syndrome Caused by the A117V Mutation of PRNP

Wenbin Yang,¹ Julie Cook,¹ Benjamin Rassbach,¹ Azucena Lemus,² Stephen J. DeArmond,² and James A. Mastrianni¹

¹Department of Neurology, University of Chicago, Chicago, Illinois 60637, and ²Department of Neuropathology, University of California, San Francisco, San Francisco, California 94143

Correspondence should be addressed to James A. Mastrianni, Department of Neurology, University of Chicago, MC2030, 5841 South Maryland Avenue, Chicago, IL 60637. Email: jmastria{at}uchicago.edu

Gerstmann–Sträussler–Scheinker syndrome (GSS) is a genetic prion disease typified clinically by the development of progressive ataxia and dementia, and histopathologically by the presence of prion protein (PrP) amyloid plaques in the CNS, especially within the cerebellum. Several mutations of the PrP gene (PRNP) are associated with GSS, but only the P102L mutation has been convincingly modeled in transgenic (Tg) mice. To determine whether other mutations carry specific GSS phenotypic information, we constructed Tg mice that express PrP carrying the mouse homolog of the GSS-associated A117V mutation. Tg(A116V) mice express approximately six times the endogenous levels of PrP, develop progressive ataxia by 140 d, and die by 170 d. Compared with a mouse model of transmissible Creutzfeldt–Jakob disease (CJD), the ataxia of Tg(A116V) mice is more prominent, and the course of disease is more protracted, paralleling that observed in human disease. Neuropathology includes mild scattered vacuolation and prominent, mainly cerebellar localized, thioflavin S-positive PrP plaques comprised of full-length PrP^A116V. In some mice, more prominent vacuolation or a noncerebellar distribution of PrP plaques was evident, suggesting some variability in phenotype. The biophysical properties of PrP from Tg(A116V) mice and human GSS(A117V) revealed a similarly low fraction of insoluble PrP and a weakly protease-resistant 13 kDa midspan PrP fragment, not observed in CJD. Overall, Tg(A116V) mice recapitulate many clinicopathologic features of GSS(A117V) that are distinct from CJD, supporting PrP^A116V to carry specific phenotypic information. The occasional variation in histopathology they exhibit may shed light on a similar observation in human GSS(A117V).

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Received June 2, 2009; revised June 30, 2009; accepted July 3, 2009.

Correspondence should be addressed to James A. Mastrianni, Department of Neurology, University of Chicago, MC2030, 5841 South Maryland Avenue, Chicago, IL 60637. Email: jmastria{at}uchicago.edu

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