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Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease

Nature Genetics volume 32, pages 420–425 (2002)Cite this article

Abstract

Mice that are homozygous with respect to a mutation (axJ) in the ataxia (ax) gene develop severe tremors by 2–3 weeks of age followed by hindlimb paralysis and death by 6–10 weeks of age1. Here we show that ax encodes ubiquitin-specific protease 14 (Usp14). Ubiquitin proteases are a large family of cysteine proteases that specifically cleave ubiquitin conjugates. Although Usp14 can cleave a ubiquitin-tagged protein in vitro, it is unable to process polyubiquitin2, which is believed to be associated with the protein aggregates seen in Parkinson disease3, spinocerebellar ataxia type 1 (SCA1; ref. 4) and gracile axonal dystrophy (GAD)5. The physiological substrate of Usp14 may therefore contain a mono-ubiquitin side chain, the removal of which would regulate processes such as protein localization6 and protein activity7,8. Expression of Usp14 is significantly altered in axJ/axJ mice as a result of the insertion of an intracisternal-A particle (IAP) into intron 5 of Usp14. In contrast to other neurodegenerative disorders such as Parkinson disease and SCA1 in humans and GAD in mice, neither ubiquitin-positive protein aggregates nor neuronal cell loss is detectable in the central nervous system (CNS) of axJ mice. Instead, axJ mice have defects in synaptic transmission in both the central and peripheral nervous systems. These results suggest that ubiquitin proteases are important in regulating synaptic activity in mammals.

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Figure 1: Meiotic and physical linkage maps of the axJ critical region.
Figure 2: Expression of Usp14 is altered in axJ mice.
Figure 3: IAP insertion into the Usp14 genomic locus.
Figure 4: In situ hybridization of Usp14.
Figure 5: Synaptic transmission at the NMJ is altered in axJ/axJ mice.
Figure 6: Analysis of short- and long-term synaptic plasticity in hippocampal area CA1 of axJ/axJ mice and their wildtype littermate controls (+/+).

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References

  1. MGD. Mouse Genomics Informatics Project (The Jackson Laboratory, Bar Harbor, Maine, 2001).

  2. Yin, L., Krantz, B., Russell, N.S., Deshpande, S. & Wilkinson, K.D. Nonhydrolyzable diubiquitin analogues are inhibitors of ubiquitin conjugation and deconjugation. Biochemistry 39, 10001–10010 (2000).

    Article  CAS  Google Scholar 

  3. McNaught, K.S., Olanow, C.W., Halliwell, B., Isacson, O. & Jenner, P. Failure of the ubiquitin–proteasome system in Parkinson's disease. Nat. Rev. Neurosci. 2, 589–594 (2001).

    Article  CAS  Google Scholar 

  4. Skinner, P.J. et al. Ataxin-1 with an expanded glutamine tract alters nuclear matrix-associated structures. Nature 389, 971–974 (1997).

    Article  CAS  Google Scholar 

  5. Saigoh, K. et al. Intragenic deletion in the gene encoding ubiquitin carboxy-terminal hydrolase in gad mice. Nat. Genet. 23, 47–51 (1999).

    Article  CAS  Google Scholar 

  6. Katzmann, D.J., Babst, M. & Emr, S.D. Ubiquitin-dependent sorting into the multivesicular body pathway requires the function of a conserved endosomal protein sorting complex, ESCRT-I. Cell 106, 145–155 (2001).

    Article  CAS  Google Scholar 

  7. Hicke, L. Protein regulation by monoubiquitination. Nat. Rev. Mol. Cell Biol. 2, 195–201 (2001).

    Article  CAS  Google Scholar 

  8. Shih, S.C., Sloper-Mould, K.E. & Hicke, L. Monoubiquitin carries a novel internalization signal that is appended to activated receptors. EMBO J. 19, 187–198 (2000).

    Article  CAS  Google Scholar 

  9. D'Amato, C.J. & Hicks, S.P. Neuropathologic alterations in the ataxia (paralytic) mouse. Arch. Pathol. 80, 604–612 (1965).

    CAS  PubMed  Google Scholar 

  10. Royaux, I., Bernier, B., Montgomery, J.C., Flaherty, L. & Goffinet, A.M. Reln(rl-Alb2), an allele of reeler isolated from a chlorambucil screen, is due to an IAP insertion with exon skipping. Genomics 42, 479–482 (1997).

    Article  CAS  Google Scholar 

  11. Hamilton, B.A. et al. The vibrator mutation causes neurodegeneration via reduced expression of PITPα: positional complementation cloning and extragenic suppression. Neuron 18, 711–722 (1997).

    Article  CAS  Google Scholar 

  12. Burt, A.M. Morphologic abnormalities in the postnatal differentiation of CA1 pyramidal cells and granule cells in the hippocampal formation of the ataxic mouse. Anat. Rec. 196, 61–69 (1980).

    Article  CAS  Google Scholar 

  13. DiAntonio, A. et al. Ubiquitination-dependent mechanisms regulate synaptic growth and function. Nature 412, 449–452 (2001).

    Article  CAS  Google Scholar 

  14. Sellin, L.C., Molgo, J., Tornquist, K., Hansson, B. & Thesleff, S. On the possible origin of giant or slow-rising miniature end-plate potentials at the neuromuscular junction. Pflugers Arch. 431, 325–334 (1996).

    Article  CAS  Google Scholar 

  15. Wilson, D.F. Influence of presynaptic receptors on neuromuscular transmission in rat. Am. J. Physiol. 242, C366–C372 (1982).

    Article  CAS  Google Scholar 

  16. Bhattacharyya, B.J. et al. Desensitization of mutant acetylcholine receptors in transgenic mice reduces the amplitude of neuromuscular synaptic currents. Synapse 27, 367–377 (1997).

    Article  CAS  Google Scholar 

  17. Plomp, J.J. et al. Abnormal transmitter release at neuromuscular junctions of mice carrying the tottering α1A Ca2+ channel mutation. Brain 123, 463–471 (2000).

    Article  Google Scholar 

  18. Washbourne, P. et al. Genetic ablation of the t-SNARE SNAP-25 distinguishes mechanisms of neuroexocytosis. Nat. Neurosci. 5, 19–26 (2002).

    Article  CAS  Google Scholar 

  19. Duchen, L.W. & Strich, S.J. The effects of botulinum toxin on the pattern of innervation of skeletal muscle in the mouse. Q. J. Exp. Physiol. Cogn. Med. Sci. 53, 84–89 (1968).

    CAS  PubMed  Google Scholar 

  20. Katz, B. & Thesleff, S. On the factors which determine the amplitude of the “miniature end plate potentials”. J. Physiol. 137, 267–278 (1957).

    Article  CAS  Google Scholar 

  21. Katz, B. & Miledi, R. The role of calcium in neuromuscular facilitation. J. Physiol. 195, 481–492 (1968).

    Article  CAS  Google Scholar 

  22. Matilla, A. et al. Mice lacking ataxin-1 display learning deficits and decreased hippocampal paired-pulse facilitation. J. Neurosci. 15, 5508–5516 (1998).

    Article  Google Scholar 

  23. Silva, A.J. et al. Impaired learning in mice with abnormal short-lived plasticity. Curr. Biol. 1, 1509–1518 (1996).

    Article  Google Scholar 

  24. Chain, D.G., Schwartz, J.H. & Hegde, A.N. Ubiquitin-mediated proteolysis in learning and memory. Mol. Neurobiol. 20, 125–142 (1999).

    Article  CAS  Google Scholar 

  25. Rosahl, T.W. et al. Essential functions of synapsins I and II in synaptic vesicle regulation. Nature 375, 488–493 (1995).

    Article  CAS  Google Scholar 

  26. Detera-Wadleigh, S.D. et al. A high-density genome scan detects evidence for a bipolar-disorder susceptibility locus on 13q32 and other potential loci on 1q32 and 18p11.2. Proc. Natl Acad. Sci. USA 96, 5604–5609 (1999).

    Article  CAS  Google Scholar 

  27. Schwab, S.G. et al. Support for a chromosome 18p locus conferring susceptibility to functional psychoses in families with schizophrenia, by association and linkage analysis. Am. J. Hum. Genet. 63, 1139–1152 (1998).

    Article  CAS  Google Scholar 

  28. Wilson, S.M. et al. Mutations in Cdh23 cause nonsyndromic hearing loss in waltzer mice. Genomics 74, 228–233 (2001).

    Article  CAS  Google Scholar 

  29. Hollingsworth, E.B. et al. Biochemical characterization of a filtered synaptoneurosome preparation from guinea pig cerebral cortex: cyclic adenosine 3′:5′-monophosphate-generating systems, receptors, and enzymes. J. Neurosci. 5, 2240–2253 (1985).

    Article  CAS  Google Scholar 

  30. Dionne, V.E. & Stevens, C.F. Voltage dependence of agonist effectiveness at the frog neuromuscular junction: resolution of a paradox. J. Physiol. 251, 245–270 (1975).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank L. Dobrunz and J. Wilson for critical reading of the manuscript; D. Swing, F. Dorsey, J. Dietz and R. Koogle for maintenance and care of the mice; D. Gilbert and T.N. O'Sullivan for technical assistance; K. Rogers, J. Matta and B. Smith for tissue sectioning; R. Frederickson for composition of the figures; and A. Borodovsky and H. Ploegh for providing the antibodies against Usp14. This work was supported by grants from the US National Institutes of Health (to R.J.M.) and the US National Cancer Institute and US Department of Health and Human Services (to N.G.C. and N.A.J.).

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Author notes

  1. Scott M. Wilson

    Present address: Department of Neurobiology, Civitan International Research Center, University of Alabama at Birmingham, Birmingham, Alabama, 35294-0021, USA

Authors and Affiliations

  1. Mouse Cancer Genetics Program, National Cancer Institute–Frederick, Frederick, 21702, Maryland, USA

    Scott M. Wilson, Rivka A. Rachel, Vincenzo Coppola, Lino Tessarollo, Deborah B. Householder, Neal G. Copeland & Nancy A. Jenkins

  2. Department of Molecular Pharmacology and Biological Chemistry, Northwestern University, Chicago, Illinois, USA

    Bula Bhattacharyya & Richard J. Miller

  3. Genomics Institute of the Novartis Foundation, 3115 Merryfield Row, San Diego, California, USA

    Colin F. Fletcher

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Wilson, S., Bhattacharyya, B., Rachel, R. et al. Synaptic defects in ataxia mice result from a mutation in Usp14, encoding a ubiquitin-specific protease. Nat Genet 32, 420–425 (2002). https://doi.org/10.1038/ng1006

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