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

Neurobiology of Disease (Nov 2005)

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

Affiliations

Akira Sawa: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Eiichiro Nagata: Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Siobhan Sutcliffe: Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Pratima Dulloor: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA
Matthew B. Cascio: Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Yuji Ozeki: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA
Sophie Roy: Merck Canada Co. Ltd., Canada
Christopher A. Ross: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.); Department of Neurology, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA
Solomon H. Snyder: Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.); Department of Pharmacology and Molecular Science, Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA; Corresponding author. Johns Hopkins School of Medicine, 725 North Wolfe Street, Baltimore, MD 21205, USA. Fax: +1 410 955 3623.

Journal volume & issue: Vol. 20, no. 2
pp. 267 – 274

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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