Truncated N-terminal fragments of huntingtin with expanded glutamine repeats form nuclear and cytoplasmic aggregates in cell culture |
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Authors: | Cooper JK; Schilling G; Peters MF; Herring WJ; Sharp AH; Kaminsky Z; Masone J; Khan FA; Delanoy M; Borchelt DR; Dawson VL; Dawson TM; Ross CA |
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Institution: | Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD 21205-2196, USA. |
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Abstract: | Huntington's disease (HD) is a progressive neurodegenerative disorder
caused by an expanding CAG repeat coding for polyglutamine in the
huntingtin protein. Recent data have suggested the possibility that an
N-terminal fragment of huntingtin may aggregate in neurons of patients with
HD, both in the cytoplasm, forming dystrophic neurites, and in the nucleus,
forming intranuclear neuronal inclusion bodies. An animal model of HD using
the short N-terminal fragment of huntingtin has also been found to have
intranuclear inclusions and this same fragment can aggregate in vitro . We
have now developed a cell culture model demonstrating that N-terminal
fragments of huntingtin with expanded glutamine repeats aggregate both in
the cytoplasm and in the nucleus. Neuroblastoma cells transiently
transfected with full-length huntingtin constructs with either a normal or
expanded repeat had diffuse cytoplasmic localization of the protein. In
contrast, cells transfected with truncated N-terminal fragments showed
aggregation only if the glutamine repeat was expanded. The aggregates were
often ubiquitinated. The shorter truncated product appeared to form more
aggregates in the nucleus. Cells transfected with the expanded repeat
construct but not the normal repeat construct showed enhanced toxicity to
the apoptosis- inducing agent staurosporine. These data indicate that
N-terminal truncated fragments of huntingtin with expanded glutamine
repeats can aggregate in cells in culture and that this aggregation can be
toxic to cells. This model will be useful for future experiments to test
mechanisms of aggregation and toxicity and potentially for testing
experimental therapeutic interventions.
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