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J. Cell Biol.,
Volume 143, Number 6, December 14, 1998 1457-1470
* Department of Pharmacology, University of Pennsylvania School of Medicine, 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.
Department
of Neurology, University of Iowa, Iowa City, Iowa 52240; and § Department of Biology, University of Pennsylvania, Philadelphia,
Pennsylvania 19104
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