The Unkindest Cut: Caspase-6 Cleavage of Huntingtin Produces Killer Fragment

Expansion of the polyglutamine (polyQ) tract in the huntingtin protein is necessary to cause Huntington disease, but it is not sufficient. For the protein to elicit neurodegeneration, it must be further processed by cleavage at the N-terminus. In today’s Cell, Michael Hayden and colleagues from the University of British Columbia in Vancouver pinpoint the pathognomic processing to a single caspase-6 cleavage motif in the N-terminal region of the protein. They show that ridding poly-Q expanded huntingtin protein of this cleavage site also rids the protein of its ability to cause neurodegeneration in a mouse model of Huntington disease. In fact, the caspase-6-resistant protein becomes neuroprotective against cytotoxic insults, similar to wild-type huntingtin protein. Given that caspase-6 also cleaves tau, possibly contributing to formation of neurofibrillary tangles in Alzheimer disease (Horowitz et al., 2004; Guo et al., 2004), and that abolition of a caspase cleavage site in the C-terminal of amyloid-β precursor protein (APP) can prevent toxicity of mutant APP in mice (see ARF related news story), caspase cleavage is emerging as a common theme in neurodegeneration.

From their previous work, the Hayden group knew that getting rid of all five caspase cleavage sites in the N-terminal end of huntingtin mitigated the toxicity of polyQ-expanded huntingtin (Wellington et al., 2000), but they wanted to know if a particular site or caspase were key to the disease. To find out, lead author Rona Graham and coworkers generated transgenic mice expressing polyQ-expanded htt with mutations in the four potential caspase-3 sites and/or the single caspase-6 site.

Did the lack of caspase cleavage affect neurotoxicity? In the case of the caspase-6-resistant protein, the answer was a resounding yes. Though mice expressing polyQ-expanded htt had decreases in brain weight and striatal volume, and progressive motor dysfunction in rotarod or open field activity tests, the mice expressing the caspase-6-resistant protein performed just as well as wild-type mice. Pathology in caspase-3-resistant mice, however, was similar to that seen in animals with protease-susceptible polyQ-expanded huntingtin.

As might be expected, the caspase-3-resistant mice, but not the caspase-6-resistant animals, had the 586-amino-acid caspase-6 cleavage fragment in their brains. These htt fragments accumulated early in the nucleus of striatal cells, consistent with this peptide playing a key role in neurotoxicity. While the caspase-6-resistant mice did show some nuclear accumulation of htt fragments, their appearance was delayed. These tardy fragments, presumably derived from other proteases, were not associated with any toxicity in the cells.

Normal huntingtin is neuroprotective, and the researchers showed that the caspase-6-resistant form, even with polyQ expansion, also plays this role. The protein increased resistance of cultured neurons to NMDA excitotoxicity and protected mice against brain damage caused by injection of quinolinic acid in vivo. These results suggest a link between excitotoxicity, caspase-6 cleavage of mutant htt and Huntington disease.

The findings also echo studies on caspase cleavage of the amyloid precursor protein and tau in Alzheimer disease. Recent work from Dale Bredesen’s lab showed that a caspase cleavage site in the cytosolic tail of APP is required for synaptic toxicity and cognitive impairment in transgenic mice (see ARF related news story). Although that study did not identify the caspase responsible, a study on the neuroprotective capabilities of estrogen implicated caspase-6 in increasing APP processing and toxicity (see ARF related news story), while several years ago, another group found that caspase-3 cleavage of APP is associated with elevated Aβ production and the appearance of senile plaques (see Gervais et al., 1999). These findings, together with the potential role of caspase-6 in tau and now huntingtin pathology, highlight the possibility of blocking the production of pathogenic protein fragments as a favored therapeutic strategy.—Pat McCaffrey

Comments

  1. Pat McCaffrey's coverage of this paper is excellent. The only thing I
    have to add is that it is unlikely that the active caspase, be it caspase-6 or another caspase, is selective for one protein.

    Therefore, identifying the insult activating the caspase in neurodegenerative diseases, or finding neuron-specific caspase
    inhibitors, is probably the best chance we have at inhibiting these pathways. The downstream events will be too numerous to control. It is nevertheless interesting that in the Huntington mouse model and in Bredesen's APP transgene that the generation of that one huntingtin or APP fragment is sufficient to induce neurodegeneration.

    View all comments by Andrea LeBlanc

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References

News Citations

  1. Paper Alert: Pathology Reversed by Abolishing APP Caspase Site
  2. A New Candidate Neuroprotective Mechanism for Estrogen

Paper Citations

  1. Horowitz PM, Patterson KR, Guillozet-Bongaarts AL, Reynolds MR, Carroll CA, Weintraub ST, Bennett DA, Cryns VL, Berry RW, Binder LI. Early N-terminal changes and caspase-6 cleavage of tau in Alzheimer's disease. J Neurosci. 2004 Sep 8;24(36):7895-902. PubMed.
  2. Guo H, Albrecht S, Bourdeau M, Petzke T, Bergeron C, Leblanc AC. Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer's disease. Am J Pathol. 2004 Aug;165(2):523-31. PubMed.
  3. Wellington CL, Singaraja R, Ellerby L, Savill J, Roy S, Leavitt B, Cattaneo E, Hackam A, Sharp A, Thornberry N, Nicholson DW, Bredesen DE, Hayden MR. Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. J Biol Chem. 2000 Jun 30;275(26):19831-8. PubMed.
  4. Gervais FG, Xu D, Robertson GS, Vaillancourt JP, Zhu Y, Huang J, LeBlanc A, Smith D, Rigby M, Shearman MS, Clarke EE, Zheng H, Van Der Ploeg LH, Ruffolo SC, Thornberry NA, Xanthoudakis S, Zamboni RJ, Roy S, Nicholson DW. Involvement of caspases in proteolytic cleavage of Alzheimer's amyloid-beta precursor protein and amyloidogenic A beta peptide formation. Cell. 1999 Apr 30;97(3):395-406. PubMed.

Further Reading

No Available Further Reading

Primary Papers

  1. Graham RK, Deng Y, Slow EJ, Haigh B, Bissada N, Lu G, Pearson J, Shehadeh J, Bertram L, Murphy Z, Warby SC, Doty CN, Roy S, Wellington CL, Leavitt BR, Raymond LA, Nicholson DW, Hayden MR. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell. 2006 Jun 16;125(6):1179-91. PubMed.

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