Huntingtin is cleaved by caspases in the cytoplasm and translocated to the nucleus via perinuclear sites in Huntington's disease patient lymphoblasts

Akira Sawa, Eiichiro Nagata, Siobhan Sutcliffe, Pratima Dulloor, Matthew B. Cascio, Yuji Ozeki, Sophie Roy, Christopher A. Ross, Solomon H. Snyder

Research output: Contribution to journalArticlepeer-review

Abstract

Accumulation of mutant Huntingtin (Htt), especially the N-terminal-cleaved Htt, participates in the pathophysiology of Huntington's disease (HD). It is difficult to elucidate temporal properties of the translocation of "endogenous" Htt using autopsy HD patient brains. Thus, we examined the cell biology of "endogenous" Htt cleavage and nuclear translocation in cultured lymphoblasts of HD patients and controls. Apoptotic stimulation of lymphoblasts elicits caspase-dependent cleavage and selective nuclear translocation of N-terminal portions of Htt. Discrete clusters of the N-terminal Htt accumulate at unique perinuclear sites prior to nuclear translocation. Our findings suggest that caspase cleavage of Htt is cytoplasmic and precedes sorting to specific perinuclear sites followed by nuclear translocation in HD patient tissue.

Original languageEnglish (US)
Pages (from-to)267-274
Number of pages8
JournalNeurobiology of Disease
Volume20
Issue number2
DOIs
StatePublished - Nov 1 2005

Keywords

  • Caspase
  • Cleavage
  • Htt
  • Huntington's disease
  • Perinuclear site

ASJC Scopus subject areas

  • Neurology

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