title: Huntingtin is cleaved by caspases in the cytoplasm and translocated to the nucleus via perinuclear sites in Huntington's disease patient lymphoblasts.
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.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
authors.forename: Akira
authors.initials: A
authors.lastname: Sawa
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Nagata
authors.forename: Siobhan
authors.initials: S
authors.lastname: Sutcliffe
authors.forename: Pratima
authors.initials: P
authors.lastname: Dulloor
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Cascio
authors.forename: Yuji
authors.initials: Y
authors.lastname: Ozeki
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.forename: Solomon H
authors.initials: SH
authors.lastname: Snyder
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000502:physiology; D017209:Apoptosis / Q000502:physiology; D020169:Caspases / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism* / Q000503:physiopathology; D008214:Lymphocytes / Q000378:metabolism* / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D013234:Stem Cells / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020169:Caspases