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The Journal of Neuroscience, November 10, 2004, 24(45):10266-10279; doi:10.1523/JNEUROSCI.2734-04.2004

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Neurobiology of Disease
A Mutant Ataxin-3 Putative-Cleavage Fragment in Brains of Machado-Joseph Disease Patients and Transgenic Mice Is Cytotoxic above a Critical Concentration

Daniel Goti,^1 * Scott M. Katzen,^1 * Jesse Mez,^1 * Noam Kurtis,¹ Jennifer Kiluk,¹ Lea Ben-Haïem,² Nancy A. Jenkins,³ Neal G. Copeland,³ Akira Kakizuka,⁴ Alan H. Sharp,⁵ Christopher A. Ross,⁶ Peter R. Mouton,⁷ and Veronica Colomer¹

¹Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, ²Institut de Génétique et de Biologie Moléculaire et Cellulaire, 67404 Illkirch Cedex, France, ³Mouse Cancer Genetics Program, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, Maryland 21702, ⁴Laboratory of Functional Biology, Kyoto University, Kyoto 606-8501, Japan, ⁵Department of General Medical Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, ⁶Division of Neurobiology, Department of Psychiatry, and Departments of Neurology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, and ⁷Stereology Resource Center, Inc., Chester, Maryland 21619

Machado-Joseph disease (MJD) is an inherited neurodegenerative disorder caused by ataxin-3 with a polyglutamine expansion. It is proposed that a toxic cleavage fragment of mutant ataxin-3 alternatively spliced isoform mjd1a triggers neurodegeneration, although this fragment has not yet been detected in the brains of MJD patients or in animal models. We have now generated transgenic mice expressing human mutant (Q71) or normal (Q20) ataxin-3 mjd1a under the control of the mouse prion promoter. Q71 transgenic mice expressing mutant ataxin-3 mjd1a above a critical level developed a phenotype similar to MJD including progressive postural instability, gait and limb ataxia, weight loss, premature death, neuronal intranuclear inclusions, and decreased tyrosine hydroxylase-positive neurons in the substantia nigra (determined by unbiased stereology). Q20 transgenic mice had normal behavior and pathology. Brains from sick Q71 transgenic mice contained an abundant mutant ataxin-3 mjd1a putative-cleavage fragment (Fragment), which was scarce in normal Q71 transgenic mice. Reactivity of the Fragment with a panel of antibodies and comigration with truncations of mutant ataxin-3 revealed that it contained residues C terminal to amino acid 221 to include the polyglutamine expansion. A similar portion of mutant ataxin-3 mjd1a expressed in transfected neuroblastoma cells was toxic above a critical concentration. The Fragment was more abundant in two affected brain regions of MJD patients. Thus, we have developed a murine model for mutant ataxin-3 mjd1a toxicity and identified a putative-cleavage fragment of the disease protein in the brains of these transgenic mice and MJD patients that is cytotoxic above a critical concentration.

Key words: neurotoxicity; Machado-Joseph; spinocerebellar ataxia type 3; ataxin-3; mouse model; cleavage fragment

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Received July 8, 2004; revised September 12, 2004; accepted September 13, 2004.

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