Huntingtin is cleaved by caspases in the cytoplasm and translocated to the nucleus via perinuclear sites in Huntington's disease patient lymphoblasts.
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.
Sawa
Akira
A
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA.
Nagata
Eiichiro
E
Sutcliffe
Siobhan
S
Dulloor
Pratima
P
Cascio
Matthew B
MB
Ozeki
Yuji
Y
Roy
Sophie
S
Ross
Christopher A
CA
Snyder
Solomon H
SH
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
C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D020169:Caspases