Abstract
Apoptosis has recently been recognized as a mode of cell death in Huntington disease (HD). Apopain, a human counterpart of the nematode cysteine protease death–gene product, CED–3, has a key role in proteolytic events leading to apoptosis. Here we show that apoptotic extracts and apopain itself specifically cleave the HD gene product, huntingtin. The rate of cleavage increases with the length of the huntingtin polyglutamine tract, providing an explanation for the gain–of–function associated with GAG expansion. Our results show that huntingtin is cleaved by cysteine proteases and suggest that HD might be a disorder of inappropriate apoptosis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Martin, S.J. & Green, D.R., Protease Activation during Apoptosis: Death by a Thousand Cuts?. Cell 82, 349–352 (1995).
Ellis, H.M. & Horvitz, H.R. Genetic control of programmed cell death in the nematode Caenorhabditis elegans. Cell 44, 817–829 (1986).
Yuan, J.-Y. et al. The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1β-converting enzyme. Cell 75, 641–652 (1993).
Nicholson, D.W. et al. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376, 37–43 (1995).
Tewari, M. et al. Yama/CPP32β, a Mammalian Homolog of CED-3, Is a CrmA-lnhibitable Protease That Cleaves the Death Substrate Poly(ADP-Ribose) Polymerase. Cell 81, 801–809 (1995).
Fernandes-Alnemri, T. Litwack, G. & Alnemri, E.S. CPP32, a novel human apoptotic protein with homology to Caenorhabditis elegans cell death protein Ced-3 and mammalian interleukin-1βp converting enzyme. J. Biol. Chem. 270, 15870–15976 (1994).
Casciola-Rosen, L.A., Grant, J.A. & Rosen, A. DNA-dependent protein kinase is one of a subset of autoantigens specifically cleaved early during apoptosis. J. Exp. Med. 182, 1625–1634 (1995).
Wang, X. et al. Cleavage of sterol regulatory element binding proteins (SREBPs) by CPP32 during apoptosis. EMBO J. 15, 1012–1020 (1996).
Hayden, M.R., Huntington's Chorea.(London: Springer-Verlag, 1981).
Harper, P.S., Huntington's Disease. (London: W. B. Saunders, 1991).
A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72, 971–983 (1993).
Kremer, H.P.H. et al. Worldwide Study of the Huntington's disease mutation: the sensitivity and specificity of repeated CAG sequences. N. Engl. J. Med. 330, 1401–1406 (1994).
Sharp, A. et al. Widespread expression of Huntington's disease gene (IT-15) protein product. Neuron. 14, 1065–1074 (1995).
DiFiglia, M. et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron. 14, 1075–1081 (1995).
Trottier, Y. et al. Polyglutamine expansion as a common pathological epitope detected in Huntington's disease, in spinocerebellar ataxia 1 and 3 and two additional autosomal dominant cerebellar ataxias. Nature 378, 403–406 (1995).
Gutekunst, C.-A. et al. Identification and localization of huntingtin in brain and human lymphoblastoid cell lines with anti-fusion protein antibodies. Proc. Natl. Acad. Sci. USA 92, 8710–8714 (1995).
Burke, J.R. et al. Huntingtin and DRPLA proteins selectively interact with the enzyme GAPDH. Nature Med. 2, 347–350 (1996).
Jou, Y.S. & Myers, R.M. Evidence from antibody studies that the CAG repeat in the Huntington disease gene is expressed in the protein. Hum. Mol. Genet. 4, 465–469 (1995).
Thomas, L.B. et al. DNA End Labeling (TUNEL) in Huntington's Disease and Other Neuropathological Conditions. Exp. Neurol. 133, 265–272 (1995).
Dragunow, M. et al. In situ evidence for DMA fragmentation in Huntington's disease striatum and Alzheimer's disease temporal lobes. Clin. Neurosci. Neuropath. 6, 1053–1057 (1995).
Protera-Cailliau, C., Hedreen, J.C., Price, D.L. & Koliatsos, V.E. Evidence for Apoptotic Cell Death in Huntington Disease and Excitotoxic Animal Models. J. Neurosci. 15, 3775–3787 (1995).
Nasir, J. et al. Targeted disruption of the Huntington's disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell 81, 811–823 (1995).
Duyao, M.P. et al . Inactivation of the mouse Huntington's disease gene homolog Hdh. Science 269, 407–410 (1995).
Zeitlin, S., Liu, J.-P., Chapman, D.L., Papaioannou, V.E. & Efstratiadis, A. Increased apoptosis and early embryonic lethality in mice nullizygous for the Huntington's disease gene homologue. Nature Genet. 11, 155–162 (1995).
Goldberg, Y.P. et al Absence of disease phenotype and intergenerational stability of the CAG repeat in transgenic mice expressing the Huntington disease transcript. Hum. Mol. Genet. 5, 177–185 (1996).
Lazebnik, Y.A., Kaufmann, S.H., Desnoyers, S., Poirier, G.G. & Earnshaw, W.C. Cleavage of poly(ADP-ribose) polymerase by a proteinase with properties like ICE. Nature 371, 346–347 (1994).
Burright, E.N. et al. SCA1 Transgenic Mice: A Model for Neurodegeneration Caused by an Expanded CAG Trinucleotide Repeat. Cell 82, 937–948 (1995).
Thornberry, N.A. et al. A novel heterodimeric cysteine protease is required for interleukin-1β processing in monocytes. Nature 356, 768–774 (1992).
Casciola-Rosen, L.A., Miller, D.K., Anhalt, G.J & Rosen, A. Specific cleavage of the 70-kD protein component of the U1 small nuclear ribonucleoprotein is a characteristic biochemical feature of apoptotic cell death. J. Biol. Chem. 269, 30757–30760 (1994).
Nicholson, D.W. ICE/CED3-like proteases as therapeutic targets for the control of inappropriate apoptosis. Nature Biotech. 14, 297–301 (1996).
Fernandes-Alnemri, T. et al. Mch3, a novel human apoptotic cysteine protease highly related to CPP32. Cancer Res. 55, 6045–6052 (1995).
Telenius, H. et al. Molecular analysis of juvenile Huntington disease: the major influence on (CAG)n repeat length is the sex of the affected parent. Hum. Mol. Genet. 2, 1535–1540 (1993).
Bump, N.J. et al. Inhibition of ICE Family Proteases by Baculovirus Antiapoptotic Protein p35. Science. 269, 1885–1888 (1995).
Xue, D. & Horvitz, H.R. Inhibition of the Caenorhabditis elegans cell-death protease CED-3 by a CED-3 cleavage site in baculovirus p35 protein. Nature 377, 248–251 (1995).
Thornberry, N.A. Interleukin-1 beta converting enzyme. Meth. Enzymol. 244, 615–631 (1994).
Towbin, H., Staehelin, T. & Gordon, J. Electrophoretic transfer of proteins form polyacrylamide gels to nitrocellulose sheets: Procedure and some applications. Proc. Natl. Acad. Sci. USA 76, 4350–4354 (1979).
Kaufmann, S.H., Desnoyers, S., Ottaviano, Y., Davidson, N.E., Poirier, G.G. Specific Proteolytic Cleavage of Poly (ADP-ribose) Polymerase: An Early Marker of Chemotherapy-induced Apoptosis. Cancer Res. 53, 3976–3985 (1993)
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Goldberg, Y., Nicholson, D., Rasper, D. et al. Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. Nat Genet 13, 442–449 (1996). https://doi.org/10.1038/ng0896-442
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0896-442
This article is cited by
-
Proteinopathies associated to repeat expansion disorders
Journal of Neural Transmission (2022)
-
Withaferin A Induces Heat Shock Response and Ameliorates Disease Progression in a Mouse Model of Huntington’s Disease
Molecular Neurobiology (2021)
-
Pyroptotic cell death in the R6/2 mouse model of Huntington’s disease: new insight on the inflammasome
Cell Death Discovery (2020)
-
Endogenous mouse huntingtin is highly abundant in cranial nerve nuclei, co-aggregates to Abeta plaques and is induced in reactive astrocytes in a transgenic mouse model of Alzheimer’s disease
Acta Neuropathologica Communications (2019)
-
Therapeutic approaches to Huntington disease: from the bench to the clinic
Nature Reviews Drug Discovery (2018)