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Cayman Ataxia-Related Protein is a Presynapse-Specific Caspase-3 Substrate

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Abstract

Caspase plays an important role in apoptosis and physiological processes such as synaptic plasticity. However, the caspase substrate at the synapse is still unknown. Here we used an in vitro cleavage assay with a small-pool human brain cDNA library. We identified the presynaptic protein Caytaxin as a substrate of caspase-3 and caspase-7. Deficiency in Caytaxin causes Cayman ataxia, a disorder characterized by cerebellar dysfunction and mental retardation. Caytaxin cleavage in cerebellar granule neurons is dependent on caspase-3 activation. The cleavage site is upstream of the cellular retinal and the TRIO guanine exchange factor domain, producing a C-terminal fragment that may play an alternative role in inhibiting MEK2 signaling. Thus, we concluded that Caytaxin is a novel substrate of caspase-3 at the presynapse.

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Abbreviations

CRAL-TRIO:

Cellular retinal and the TRIO guanine exchange factor

BCH:

BNIP-2 and Cdc42GAP homology

MAPK:

Mitogen-activated protein kinase

ERK:

Extracellular signal-regulated kinase

CA-MEK2:

Constitutively active MAPK/ERK kinase 2

GAP:

GTPase-activating protein

KGA:

Kidney-type glutaminase

GFP:

Green fluorescent protein

DMEM:

Dulbecco’s modified Eagle’s medium

FBS:

Fetal bovine serum

GA:

Glutaraldehyde

PFA:

Paraformaldehyde

References

  1. Kuranaga E, Kanuka H, Tonoki A, Takemoto K, Tomioka T et al (2006) Drosophila IKK-related kinase regulates nonapoptotic function of caspases via degradation of IAPs. Cell 126:583–596

    Article  PubMed  CAS  Google Scholar 

  2. D’Amelio M, Cavallucci V, Cecconi F (2010) Neuronal caspase-3 signaling: not only cell death. Cell Death Differ 17:1104–1114

    Article  PubMed  Google Scholar 

  3. Yi CH, Yuan J (2009) The Jekyll and Hyde functions of caspases. Dev Cell 16:21–34

    Article  PubMed  CAS  Google Scholar 

  4. Kudryashova IV, Onufriev MV, Kudryashov IE, Gulyaeva NV (2009) Caspase-3 activity in hippocampal slices reflects changes in synaptic plasticity. Neurosci Behav Physiol 39:13–20

    Article  PubMed  CAS  Google Scholar 

  5. Bravarenko NI, Onufriev MV, Stepanichev MY, Ierusalimsky VN, Balaban PM et al (2006) Caspase-like activity is essential for long-term synaptic plasticity in the terrestrial snail Helix. Eur J Neurosci 23:129–140

    Article  PubMed  CAS  Google Scholar 

  6. Huesmann GR, Clayton DF (2006) Dynamic role of postsynaptic caspase-3 and BIRC4 in zebra finch song-response habituation. Neuron 52:1061–1072

    Article  PubMed  CAS  Google Scholar 

  7. Fernando P, Brunette S, Megeney LA (2005) Neural stem cell differentiation is dependent upon endogenous caspase 3 activity. Faseb J 19:1671–1673

    PubMed  CAS  Google Scholar 

  8. Williams DW, Kondo S, Krzyzanowska A, Hiromi Y, Truman JW (2006) Local caspase activity directs engulfment of dendrites during pruning. Nat Neurosci 9:1234–1236

    Article  PubMed  CAS  Google Scholar 

  9. Nikolaev A, McLaughlin T, O’Leary DD, Tessier-Lavigne M (2009) APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature 457:981–989

    Article  PubMed  CAS  Google Scholar 

  10. Arama E, Bader M, Rieckhof GE, Steller H (2007) A ubiquitin ligase complex regulates caspase activation during sperm differentiation in Drosophila. PLoS Biol 5:e251

    Article  PubMed  Google Scholar 

  11. Geisbrecht ER, Montell DJ (2004) A role for Drosophila IAP1-mediated caspase inhibition in Rac-dependent cell migration. Cell 118:111–125

    Article  PubMed  CAS  Google Scholar 

  12. Li J, Brieher WM, Scimone ML, Kang SJ, Zhu H et al (2007) Caspase-11 regulates cell migration by promoting Aip1-Cofilin-mediated actin depolymerization. Nat Cell Biol 9:276–286

    Article  PubMed  CAS  Google Scholar 

  13. Louneva N, Cohen JW, Han LY, Talbot K, Wilson RS et al (2008) Caspase-3 is enriched in postsynaptic densities and increased in Alzheimer’s disease. Am J Pathol 173:1488–1495

    Article  PubMed  CAS  Google Scholar 

  14. Li Z, Jo J, Jia JM, Lo SC, Whitcomb DJ et al (2010) Caspase-3 activation via mitochondria is required for long-term depression and AMPA receptor internalization. Cell 141:859–871

    Article  PubMed  CAS  Google Scholar 

  15. Mattson MP, Keller JN, Begley JG (1998) Evidence for synaptic apoptosis. Exp Neurol 153:35–48

    Article  PubMed  CAS  Google Scholar 

  16. Mattson MP, Partin J, Begley JG (1998) Amyloid beta-peptide induces apoptosis-related events in synapses and dendrites. Brain Res 807:167–176

    Article  PubMed  CAS  Google Scholar 

  17. D’Amelio M, Cavallucci V, Middei S, Marchetti C, Pacioni S et al (2011) Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer’s disease. Nat Neurosci 14:69–76

    Article  PubMed  Google Scholar 

  18. Glantz LA, Gilmore JH, Lieberman JA, Jarskog LF (2006) Apoptotic mechanisms and the synaptic pathology of schizophrenia. Schizophr Res 81:47–63

    Article  PubMed  Google Scholar 

  19. Bomar JM, Benke PJ, Slattery EL, Puttagunta R, Taylor LP et al (2003) Mutations in a novel gene encoding a CRAL-TRIO domain cause human Cayman ataxia and ataxia/dystonia in the jittery mouse. Nat Genet 35:264–269

    Article  PubMed  CAS  Google Scholar 

  20. Xiao J, Ledoux MS (2005) Caytaxin deficiency causes generalized dystonia in rats. Brain Res Mol Brain Res 141:181–192

    Article  PubMed  CAS  Google Scholar 

  21. LeDoux MS, Lorden JF (2002) Abnormal spontaneous and harmaline-stimulated Purkinje cell activity in the awake genetically dystonic rat. Exp Brain Res 145:457–467

    Article  PubMed  Google Scholar 

  22. Hayakawa Y, Itoh M, Yamada A, Mitsuda T, Nakagawa T (2007) Expression and localization of Cayman ataxia-related protein, Caytaxin, is regulated in a developmental- and spatial-dependent manner. Brain Res 1129:100–109

    Article  PubMed  CAS  Google Scholar 

  23. Buschdorf JP, Li Chew L, Zhang B, Cao Q, Liang FY et al (2006) Brain-specific BNIP-2-homology protein Caytaxin relocalises glutaminase to neurite terminals and reduces glutamate levels. J Cell Sci 119:3337–3350

    Article  PubMed  CAS  Google Scholar 

  24. Buschdorf JP, Chew LL, Soh UJ, Liou YC, Low BC (2008) Nerve growth factor stimulates interaction of Cayman ataxia protein BNIP-H/Caytaxin with peptidyl-prolyl isomerase Pin1 in differentiating neurons. PLoS One 3:e2686

    Article  PubMed  Google Scholar 

  25. McAllister AK (2007) Dynamic aspects of CNS synapse formation. Annu Rev Neurosci 30:425–450

    Article  PubMed  CAS  Google Scholar 

  26. Sudhof TC (2004) The synaptic vesicle cycle. Annu Rev Neurosci 27:509–547

    Article  PubMed  Google Scholar 

  27. Rohrbough J, Broadie K (2005) Lipid regulation of the synaptic vesicle cycle. Nat Rev Neurosci 6:139–150

    Article  PubMed  CAS  Google Scholar 

  28. Jovanovic JN, Benfenati F, Siow YL, Sihra TS, Sanghera JS et al (1996) Neurotrophins stimulate phosphorylation of synapsin I by MAP kinase and regulate synapsin I-actin interactions. Proc Natl Acad Sci USA 93:3679–3683

    Article  PubMed  CAS  Google Scholar 

  29. Jovanovic JN, Czernik AJ, Fienberg AA, Greengard P, Sihra TS (2000) Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat Neurosci 3:323–329

    Article  PubMed  CAS  Google Scholar 

  30. Giachello CN, Fiumara F, Giacomini C, Corradi A, Milanese C et al (2010) MAPK/Erk-dependent phosphorylation of synapsin mediates formation of functional synapses and short-term homosynaptic plasticity. J Cell Sci 123:881–893

    Article  PubMed  CAS  Google Scholar 

  31. Kushner SA, Elgersma Y, Murphy GG, Jaarsma D, van Woerden GM et al (2005) Modulation of presynaptic plasticity and learning by the H-ras/extracellular signal-regulated kinase/synapsin I signaling pathway. J Neurosci 25:9721–9734

    Article  PubMed  CAS  Google Scholar 

  32. Vara H, Onofri F, Benfenati F, Sassoe-Pognetto M, Giustetto M (2009) ERK activation in axonal varicosities modulates presynaptic plasticity in the CA3 region of the hippocampus through synapsin I. Proc Natl Acad Sci USA 106:9872–9877

    Article  PubMed  CAS  Google Scholar 

  33. Cui Y, Costa RM, Murphy GG, Elgersma Y, Zhu Y et al (2008) Neurofibromin regulation of ERK signaling modulates GABA release and learning. Cell 135:549–560

    Article  PubMed  CAS  Google Scholar 

  34. Zhou YT, Guy GR, Low BC (2005) BNIP-2 induces cell elongation and membrane protrusions by interacting with Cdc42 via a unique Cdc42-binding motif within its BNIP-2 and Cdc42GAP homology domain. Exp Cell Res 303:263–274

    Article  PubMed  CAS  Google Scholar 

  35. Thornberry NA, Rano TA, Peterson EP, Rasper DM, Timkey T et al (1997) A combinatorial approach defines specificities of members of the caspase family and granzyme B. Functional relationships established for key mediators of apoptosis. J Biol Chem 272:17907–17911

    Article  PubMed  CAS  Google Scholar 

  36. Caballero-Benitez A, Moran J (2003) Caspase activation pathways induced by staurosporine and low potassium: role of caspase-2. J Neurosci Res 71:383–396

    Article  PubMed  CAS  Google Scholar 

  37. Aoyama T, Hata S, Nakao T, Tanigawa Y, Oka C et al (2009) Cayman ataxia protein caytaxin is transported by kinesin along neurites through binding to kinesin light chains. J Cell Sci 122:4177–4185

    Article  PubMed  CAS  Google Scholar 

  38. Wen W, Meinkoth JL, Tsien RY, Taylor SS (1995) Identification of a signal for rapid export of proteins from the nucleus. Cell 82:463–473

    Article  PubMed  CAS  Google Scholar 

  39. Valencia CA, Cotten SW, Liu R (2007) Cleavage of BNIP-2 and BNIP-XL by caspases. Biochem Biophys Res Commun 364:495–501

    Article  PubMed  CAS  Google Scholar 

  40. Gulyaeva NV, Kudryashov IE, Kudryashova IV (2003) Caspase activity is essential for long-term potentiation. J Neurosci Res 73:853–864

    Article  PubMed  CAS  Google Scholar 

  41. Morabito MA, Sheng M, Tsai LH (2004) Cyclin-dependent kinase 5 phosphorylates the N-terminal domain of the postsynaptic density protein PSD-95 in neurons. J Neurosci 24:865–876

    Article  PubMed  CAS  Google Scholar 

  42. tom Dieck S, Sanmarti-Vila L, Langnaese K, Richter K, Kindler S et al (1998) Bassoon, a novel zinc-finger CAG/glutamine-repeat protein selectively localized at the active zone of presynaptic nerve terminals. J Cell Biol 142:499–509

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

TN expresses gratitude to Professor K. Mikoshiba as my mentor for his continuous enthusiasm for medicine as well as biology, which strongly motivates me. We thank Drs B.C. Low (National University of Singapore) for the donation of KGA and Pin1 plasmids, and Y. Sakoh, T. Mitsuda, and H. Chen (Gifu University Graduate School of Medicine) for technical assistance. This work was supported in part by the Japan Brain Foundation, Takeda Science Foundation, Astellas Foundation for Research on Medical Resources, and Grant-in-Aid from the Ministry of Education, Science, Sports, and Culture of Japan.

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Authors and Affiliations

  1. Department of Neurobiology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan

    Masanori Itoh, Shimo Li, Kazunori Ohta, Aiko Yamada, Yoshika Hayakawa-Yano, Masashi Ueda, Yoko Hida, Yoshihiro Suzuki, Eri Ohta, Akihito Mizuno & Toshiyuki Nakagawa

  2. Department of Cell Signaling, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan

    Yoshiko Banno

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  1. Masanori Itoh
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Correspondence to Toshiyuki Nakagawa.

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Special Issue: In Honor of Dr. Mikoshiba.

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Itoh, M., Li, S., Ohta, K. et al. Cayman Ataxia-Related Protein is a Presynapse-Specific Caspase-3 Substrate. Neurochem Res 36, 1304–1313 (2011). https://doi.org/10.1007/s11064-011-0430-5

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