Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease

E. Hermel, J. Gafni, S. S. Propp, B. R. Leavitt, C. L. Wellington, J. E. Young, Abigail S Hackam, A. V. Logvinova, A. L. Peel, S. F. Chen, V. Hook, R. Singaraja, S. Krajewski, P. C. Goldsmith, H. M. Ellerby, M. R. Hayden, D. E. Bredesen, L. M. Ellerby

Research output: Contribution to journalArticle

168 Citations (Scopus)

Abstract

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder resulting in selective neuronal loss and dysfunction in the striatum and cortex. The molecular pathways leading to the selectivity of neuronal cell death in HD are poorly understood. Proteolytic processing of full-length mutant huntingtin (Htt) and subsequent events may play an important role in the selective neuronal cell death found in this disease. Despite the identification of Htt as a substrate for caspases, it is not known which caspase(s) cleaves Htt in vivo or whether regional expression of caspases contribute to selective neuronal cells loss. Here, we evaluate whether specific caspases are involved in cell death induced by mutant Htt and if this correlates with our recent finding that Htt is cleaved in vivo at the caspase consensus site 552. We find that caspase-2 cleaves Htt selectively at amino acid 552. Further, Htt recruits caspase-2 into an apoptosome-like complex. Binding of caspase-2 to Htt is polyglutamine repeat-length dependent, and therefore may serve as a critical initiation step in HD cell death. This hypothesis is supported by the requirement of caspase-2 for the death of mouse primary striatal cells derived from HD transgenic mice expressing full-length Htt (YAC72). Expression of catalytically inactive (dominant-negative) forms of caspase-2, caspase-7, and to some extent caspase-6, reduced the cell death of YAC72 primary striatal cells, while the catalytically inactive forms of caspase-3, -8, and -9 did not. Histological analysis of post-mortem human brain tissue and YAC72 mice revealed activation of caspases and enhanced caspase-2 immunoreactivity in medium spiny neurons of the striatum and the cortical projection neurons when compared to controls. Further, upregulation of caspase-2 correlates directly with decreased levels of brain-derived neurotrophic factor in the cortex and striatum of 3-month YAC72 transgenic mice and therefore suggests that these changes are early events in HD pathogenesis. These data support the involvement of caspase-2 in the selective neuronal cell death associated with HD in the striatum and cortex.

Original languageEnglish
Pages (from-to)424-438
Number of pages15
JournalCell Death and Differentiation
Volume11
Issue number4
DOIs
StatePublished - Apr 1 2004
Externally publishedYes

Fingerprint

Caspase 2
Huntington Disease
Caspases
Cell Death
Corpus Striatum
Transgenic Mice
Apoptosomes
Caspase 6
Caspase 7
Neurons
Caspase 8
Brain-Derived Neurotrophic Factor
Caspase 3
Neurodegenerative Diseases
Up-Regulation
Amino Acids

Keywords

  • Apoptosis
  • Caspase
  • Huntington's disease
  • Polyglutamine

ASJC Scopus subject areas

  • Cell Biology

Cite this

Hermel, E., Gafni, J., Propp, S. S., Leavitt, B. R., Wellington, C. L., Young, J. E., ... Ellerby, L. M. (2004). Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease. Cell Death and Differentiation, 11(4), 424-438. https://doi.org/10.1038/sj.cdd.4401358

Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease. / Hermel, E.; Gafni, J.; Propp, S. S.; Leavitt, B. R.; Wellington, C. L.; Young, J. E.; Hackam, Abigail S; Logvinova, A. V.; Peel, A. L.; Chen, S. F.; Hook, V.; Singaraja, R.; Krajewski, S.; Goldsmith, P. C.; Ellerby, H. M.; Hayden, M. R.; Bredesen, D. E.; Ellerby, L. M.

In: Cell Death and Differentiation, Vol. 11, No. 4, 01.04.2004, p. 424-438.

Research output: Contribution to journalArticle

Hermel, E, Gafni, J, Propp, SS, Leavitt, BR, Wellington, CL, Young, JE, Hackam, AS, Logvinova, AV, Peel, AL, Chen, SF, Hook, V, Singaraja, R, Krajewski, S, Goldsmith, PC, Ellerby, HM, Hayden, MR, Bredesen, DE & Ellerby, LM 2004, 'Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease', Cell Death and Differentiation, vol. 11, no. 4, pp. 424-438. https://doi.org/10.1038/sj.cdd.4401358
Hermel, E. ; Gafni, J. ; Propp, S. S. ; Leavitt, B. R. ; Wellington, C. L. ; Young, J. E. ; Hackam, Abigail S ; Logvinova, A. V. ; Peel, A. L. ; Chen, S. F. ; Hook, V. ; Singaraja, R. ; Krajewski, S. ; Goldsmith, P. C. ; Ellerby, H. M. ; Hayden, M. R. ; Bredesen, D. E. ; Ellerby, L. M. / Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington's disease. In: Cell Death and Differentiation. 2004 ; Vol. 11, No. 4. pp. 424-438.
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