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© The Rockefeller University Press, 0021-9525/1998//1457 $5.00
The Journal of Cell Biology, Volume 143, Number 6, , 1998 1457-1470

Recruitment and the Role of Nuclear Localization in Polyglutamine-mediated Aggregation

Matthew K. Perez^*, Henry L. Paulson, Sagun J. Pendse^*, Sarah J. Saionz^*, Nancy M. Bonini, and Randall N. Pittman^*

^* Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104; Department of Neurology, University of Iowa, Iowa City, Iowa 52240; and Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104

The inherited neurodegenerative diseases caused by an expanded glutamine repeat share the pathologic feature of intranuclear aggregates or inclusions (NI). Here in cell-based studies of the spinocerebellar ataxia type-3 disease protein, ataxin-3, we address two issues central to aggregation: the role of polyglutamine in recruiting proteins into NI and the role of nuclear localization in promoting aggregation. We demonstrate that full-length ataxin-3 is readily recruited from the cytoplasm into NI seeded either by a pathologic ataxin-3 fragment or by a second unrelated glutamine-repeat disease protein, ataxin-1. Experiments with green fluorescence protein/polyglutamine fusion proteins show that a glutamine repeat is sufficient to recruit an otherwise irrelevant protein into NI, and studies of human disease tissue and a Drosophila transgenic model provide evidence that specific glutamine-repeat–containing proteins, including TATA-binding protein and Eyes Absent protein, are recruited into NI in vivo. Finally, we show that nuclear localization promotes aggregation: an ataxin-3 fragment containing a nonpathologic repeat of 27 glutamines forms inclusions only when targeted to the nucleus. Our findings establish the importance of the polyglutamine domain in mediating recruitment and suggest that pathogenesis may be linked in part to the sequestering of glutamine-containing cellular proteins. In addition, we demonstrate that the nuclear environment may be critical for seeding polyglutamine aggregates.

Key Words: trinucleotide • triplet repeat • Machado-Joseph disease • neurodegeneration • hereditary ataxia

Abbreviations used in this paper: EYA, Eyes Absent protein; GFP, green fluorescence protein; HA, hemagglutinin; HEK, human embryonic kidney; MJD, Machado-Joseph disease; NI, intranuclear inclusions; NLS, nuclear localization signal; SCA, spinocerebellar ataxin; TBP, TATA-binding protein.

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