Evidence for both the nucleus and cytoplasm as subcellular sites of pathogenesis in huntington's disease in cell culture and in transgenic mice expressing mutant huntingtin

Abigail S. Hackam, J. Graeme Hodgson, Roshni Singaraja, Taiqi Zhang, Lu Gan, Claire Anne Gutekunst, Steven M. Hersch, Michael R. Hayden

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

A unifying feature of the CAG expansion diseases is the formation of intracellular aggregates composed of the mutant polyglutamine-expanded protein. Despite the presence of aggregates in affected patients, the precise relationship between aggregates and disease pathogenesis is unresolved. Results from in vivo and in vitro studies of mutant huntingtin have led to the hypothesis that nuclear localization of aggregates is critical for the pathology of Huntington's disease (HD). We tested this hypothesis using a 293T cell culture model system by comparing the frequency and toxicity of cytoplasmic and nuclear huntingtin aggregates. Insertion of nuclear import or export sequences into huntingtin fragments containing 548 or 151 amino acids was used to reverse the normal localization of these proteins. Changing the subcellular localization of the fragments did not influence their total aggregate frequency. There were also no significant differences in toxicity associated with the presence of nuclear compared with cytoplasmic aggregates. These studies, together with findings in transgenic mice, suggest two phases for the pathogenesis of HD, with the initial toxicity in the cytoplasm followed by proteolytic processing of huntingtin, nuclear translocation with increased nuclear concentration of N-terminal fragments, seeding of aggregates and resultant apoptotic death. These findings support the nucleus and cytosol as subcellular sites for pathogenesis in HD.

Original languageEnglish (US)
Pages (from-to)1047-1055
Number of pages9
JournalPhilosophical Transactions of the Royal Society B: Biological Sciences
Volume354
Issue number1386
DOIs
StatePublished - Jun 29 1999
Externally publishedYes

Keywords

  • Aggregates
  • Animal model
  • Huntington's disease
  • In vitro
  • Pathogenesis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Agricultural and Biological Sciences (miscellaneous)

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