Skip to main content
SpringerLink
Log in

A human ubiquitin conjugating enzyme, L-UBC, maps in the Alzheimer's disease locus on Chromosome 14q24.3

  • Original Contributions
  • Published:
Mammalian Genome Aims and scope Submit manuscript

Abstract

We have identified a novel ubiquitin conjugating enzyme gene, L-UBC, which maps to human Chromosome (Chr) 14q24.3. This is also the location of the major early onset familial Alzheimer's disease gene (FAD3). L-UBC encodes a protein that demonstrates homology to the yeast ubiquitin conjugating enzyme, UBC-4, and human UbcH5. Their functions are to ubiquitinate specific proteins targeted for degradation. The protein also exhibits very strong homology to a rabbit protein, E2-F1, which mediates p53 degradation driven by papilloma virus E6 protein in vitro. The accumulation of specific proteins that have undergone aberrant processing in neurofibrillary tangles and amyloid plaques is the classic pathological feature in brains of Alzheimer's disease patients. Abnormal ubiquitination has previously been suggested to play a role in the etiology of Alzheimer's disease. This gene therefore represents a plausible candidate gene for FAD3.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Blumenfeld, N., Gonen, H., Mayer, A., Smith, C.E., Siegel, N.R., Schwartz, A.L., Ciechanover, A. (1994). Purification and characterisation of a novel species of ubiquitin-carrier protein E2 that is involved in degradation of non-“N-end rule” protein substrates. J. Biol. Chem. 269, 9574–9581.

    Google Scholar 

  • Chau, V., Tobias, J.W., Bachmair, A., Marriot, D., Ecker, D.J., Gonda, D.K., Varshavsky, A. (1989). A multi-ubiquitin chain is confined to specific lysine in a targeted short-lived protein. Science 243, 1576–1583.

    Google Scholar 

  • Chowdary, D.R., Dermody, J.J., Jha, K.K., Ozer, H.L. (1994). Accumulation of p53 in a mutant cell line defective in the ubiquitin pathway. Mol. Cell. Biol. 14, 1997–2003.

    Google Scholar 

  • Ciechanover, A. (1994). The ubiquitin-proteasome proteolytic pathway. Cell 79, 13–21.

    Google Scholar 

  • Ciechanover, A., Schwartz, A.L. (1994). The ubiquitin mediated proteolytic pathway: mechanisms of recognition of the proteolytic involvement in the degradation of native cellular proteins. FASEB J 8, 182–191.

    Google Scholar 

  • Ciechanover, A., Shkedy, D., Oren, M., Bercovich, B. (1994). Degradation of the tumour suppressor protein p53 by the ubiquitin-mediated proteolytic system requires a novel species of ubiquitin-carrier protein. J. Biol. Chem. 269, 9582–9589.

    Google Scholar 

  • Crane, D.I., Kalish, J.E., Gould, S.J. (1994) The Pichia pastaris PA54 gene encodes a ubiquitin-conjugating enzyme required for peroxisome assembly. J. Biol. Chem. 269, 21835–21844.

    Google Scholar 

  • Deshaies, R.J., Chau, V., Kirschner, M. (1995). Ubiquination of the G1 cyclin Cln2p by a Cdc34p-dependent pathway. EMBO J. 14, 303–312.

    Google Scholar 

  • Garruto, R.M., Brown, P. (1994). Tau protein, aluminium, and Alzheimer's disease. Lancet 343, 989.

    Google Scholar 

  • Goate, A., Chartier-Harlin, M.C., Mullan, M., Brown, J., Crawford, F., Fidani, L., Giuffra, L., Haynes, A., Irving, N., James, L., Mant, R., Newton, P., Rooke, K., Roques, P., Talbot, C., Pericak-Vance, M., Roses, A., Williamson, R., Rosser, M., Owen, M., Hardy, J. (1991). Segregation of a mis-sense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704–706.

    Google Scholar 

  • Goedert, M., Spillantini, M.G., Cairns, N.J., Crowther, R.A. (1992). Tau proteins of Alzheimer paired helical filaments: abnormal phosphorylation of all six brain isoforms. Neuron 8, 159–168.

    Google Scholar 

  • Goldberg, A.L., Rock, K.L. (1992) Proteolysis, proteosomes and antigen presentation. Nature 357, 375–379.

    Google Scholar 

  • Haas, A.L., Rose, I.A. (1992) The mechanism of ubiquitin activating enzyme. J. Biol. Chem. 257, 10329–10337.

    Google Scholar 

  • Haas, C., Koo, E., Mellon, A., Hung, A.Y., Selkoe, D. (1992). Targeting of cell surface β amyloid precursor protein to lysosomes: alternative processing into amyloid bearing fragments. Nature 357, 500–503.

    Google Scholar 

  • Haas, C., Hung, A.Y., Selkoe, D.J., Teplow, D.B. (1994) Mutations associated with a locus for familial Alzheimer's disease result in alternative processing of amyloid β protein precursor. J. Biol. Chem. 269, 17741–17748.

    Google Scholar 

  • Handley, P.M., Mueckler, M., Siegel, N.R., Ciechanover, A., Schwartz, A.L. (1991) Molecular cloning, sequence and tissue distribution of the human ubiquitin conjugating enzyme E1. Proc. Natl. Acad. Sci. USA 88, 258–262.

    Google Scholar 

  • Hardy, J.A., Higgins, G.A. (1992). Alzheimer's disease: the amyloid cascade hypothesis. Science 256, 184–185.

    Google Scholar 

  • Harrington, C.R., Wischik, C.M., McArthur, F.K., Taylor, G.A., Edwardson, J.A., Candy, J.M. (1994) Alzheimer's disease-like changes in tau protein processing: association with aluminium accumulation in brains of renal dialysis patients. Lancet 343, 993–997.

    Google Scholar 

  • Hershko, A., Ciechanover, A. (1992) The ubiquitin system for protein degradation. Annu. Rev. Biochem. 61, 761–807.

    Google Scholar 

  • Jalal, S.M., Law, M.E., Christensen, E.R., Spurbeck, J.L., Dewald, G.W. (1993) Method for sequential staining of GTL-banded metaphases with fluorescent-labelled chromosome specific paint probes. Am. J. Med. Genet. 46, 98–103.

    Google Scholar 

  • Jentsch, S. (1992) The ubiquitin conjugation system. Annu. Rev. Genet. 26, 179–207.

    Google Scholar 

  • Jentsch, S., Seufert, W., Sommer, T., Reins, H.J. (1990) Ubiquitin conjugating enzymes: novel regulators of eukaryotic cells. Trends Biochem. Sci. 15, 195–198.

    Google Scholar 

  • Jentsch, S., Seufert, W., Hauser, H.P. (1991) Genetic analysis of the ubiquitin system. Biochim. Biophys. Acta 1098, 127–139.

    Google Scholar 

  • Kaiser, P., Seufert, W., Hofferer, L., Kofler, B., Sachsenmaier, C., Herzog, H., Jentsch, S., Schweiger, M., Schneider, R. (1994) A human ubiquitin conjugating enzyme homologous to yeast UBC-8. J. Biol. Chem. 269, 8797–8802.

    Google Scholar 

  • Kawashima, M.M., Hasegawa, M., Takio, K., Suzuki, M., Titani, K., Ihara, Y. (1993) Ubiquitin is conjugated with amino terminally processed tau in paired helical filaments. Neuron 10, 1151–1160.

    Google Scholar 

  • Kay, G.F., Ashworth, A., Penny, G.D., Dunlop, M., Swift, S., Brockdorff, N., Rastan, S. (1991). A candidate spermatogenesis gene on the mouse Y chromosome is homologous to ubiquitin activating enzyme E1. Nature 354, 486–489.

    Google Scholar 

  • Kok, K., Hofstra, R., Pilz, A., van den Berg, A., Terpstra, P., Buys, C.H.C.M., Carritt, B. (1993) A gene in the chromosomal region 3p21 with greatly reduced expression in lung cancer is similar to the gene for ubiquitin activating enzyme. Proc. Natl. Acad. Sci. USA 90, 6071–6075.

    Google Scholar 

  • Koken, M.H.M., Smit, E.M.E., Jaspers-Dekker, I., Oostra, B.A., Hagemeijer, A., Bootsma, D., Hoeijmakers, J.H.J. (1992) Localisation of two human homologues HHR6A and HHR6B, of the yeast DNA repair gene RAD6 to chromosomes Xq24-q25 and 5q23-q31. Genomics 12, 447–453.

    Google Scholar 

  • Koo, E.H., Squazzo, S.L. (1994) Evidence that production and release of amyloid β protein involves the endocytic pathway. J. Biol. Chem. 269, 17386–17389.

    Google Scholar 

  • Kyte, J., Doolittle, R.F. (1982) A simple method for displaying the hydropathic character of a protein. J. Mol. Biol. 157, 105–132.

    Google Scholar 

  • Landegent, J.E., Dewal, N.J.I., Dirk, R.W., Baas, F., Van der Ploeg, M. (1987). Use of whole cosmid cloned genomic sequences for chromosomal localisation by non-radioactive in situ hybridisation. Hum. Genet. 77, 336–370.

    Google Scholar 

  • Lowe, J., Blanchard, A., Morrell, K., Lennox, G., Reynolds, L., Billet, M., Landon, M., Mayer, R.J. (1988) Ubiquitin is a common factor in intermediate filament inclusion bodies of diverse type in man, including those of Parkinson's disease, Pick's disease, and Alzheimer's disease, as well as Rosenthal fibres in cerebellar astrocytomas, cytoplasmic bodies in muscle and Mallory bodies in alcoholic liver disease. J. Pathol. 155, 9–15.

    Google Scholar 

  • Mandelkow, E.M., Mandelkow, E. (1993) Tau as a marker for Alzheimer's disease, Trends Biochem. Sci. 18, 480–483.

    Google Scholar 

  • McKhann, G., Drachman, D., Folsteine, M., Katzman, R., Price, D., Stadlan, E.M. (1984) Clinical diagnosis of Alzheimer's disease: Report of the NINCDS-ADRDA Workgroup under the auspices of the Department of Health and Human Services Task Force on Alzheimer's Disease. Neurology 34, 939–944.

    Google Scholar 

  • Mori, H., Kond, J., Ihara, Y. (1987). Ubiquitin is a component of paired helical filaments in Alzheimer's disease. Science 235, 1641–1644.

    Google Scholar 

  • Mullan, M., Houlden, H., Windenlspecht M., Fidani, L., Lombardi, C., Diaz, P., Rosser, M., Crook, R., Hardy, J., Duff, K., Crawford, F. (1992). A locus for familial early onset Alzheimer's disease on the long arm of chromosome 14, proximal to the α-1-antichimotrypsin gene. Nature Genet. 2, 340–342.

    Google Scholar 

  • Muralidhar, M.G., Thomas, J.B. (1993) The drosophila bendless gene encodes a neural protein related to the ubiquitin-conjugating enzymes. Neuron, 11, 253–266.

    Google Scholar 

  • Palombella, V.J., Rando, O.J., Goldberg, A.L., Maniatis, T. (1994). The ubiquitin-proteasome pathway is required for processing the NF-κB1 precursor protein and the activation of NF-κB. Cell, 773–785.

  • Paolini, R., Kinet, J.-P., (1993) Cell surface control of the multiubiquination and deubiquination of high-affinity immunoglobulin E receptors. EMBO J. 12, 779–786.

    Google Scholar 

  • Papa, F.R., Hochstrasser, M. (1993) The yeast DOA-4 gene encodes deubiquitinating enzyme related to a product of the human tre-2 oncogene. Nature 366, 313–319.

    Google Scholar 

  • Perry, G.P., Friedman, R., Shaw, G., Chau, V. (1987). Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer's disease brains. Proc. Natl. Acad. Sci. USA 84, 3033–3036.

    Google Scholar 

  • Plon, S.E., Leppig, K.A., Do, H.N., Groudine, M. (1993). Cloning of the human homologue of the CDC34 cell cycle gene by complementation in yeast. Proc. Natl. Acad. Sci. USA 90, 10484–10488.

    Google Scholar 

  • Reiss, Y., Heller, H., Hershko, A. (1989) Binding sites of ubiquitin protein ligase. J. Biol. Chem. 264, 10378–10383.

    Google Scholar 

  • Robinson, P.A., Marley, J.J., High, A.S., Hume, W.J. (1994). Differential expression of protease inhibitor genes between normal human oral tissue and odontogenic keratocysts. Arch. Oral. Biol. 39, 251–259.

    Google Scholar 

  • Rolfe, M., Beer-Romero, P., Glass, S., Eckstein, J., Berdo, I., Theodoras, A., Pagano, M., Draetta, G. (1995). Reconstitution of p53-ubiquinylation reactions from purified components: the role of human ubiquitin-conjugating enzyme UBC4 and E6-associated protein (E6AP). Proc. Natl. Acad. Sci. USA 92, 3264–3268.

    Google Scholar 

  • Sambrook, J., Fritsch, E.F., Maniatis, T. (1989) Molecular Cloning: A Laboratory Manual, 2nd ed. (Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory Press).

    Google Scholar 

  • Scheffner, M., Huibregtse, J.M., Howley, P.M. (1994) Identification of a human ubiquitin-conjugating enzyme that mediates the E6-AP-dependent ubiquitination of p53. Proc. Natl. Acad. Sci. USA 91, 8797–8801.

    Google Scholar 

  • Schellenberg, G.D., Bird, T.D., Wijsman, E.M., Orr, H.T., Anderson, L., Nemens, E., White, J.A., Bonneycastle, L., Weber, J.L., Alonso, M.E., Potter, H., Heston, L.L., Martin, G.M. (1992) Genetic linkage evidence for a familial Alzheimer's disease locus on chromosome 14. Science 258, 668–671.

    Google Scholar 

  • Seufert, W., Jentsch, S. (1990) Ubiquitin conjugating enzymes UBC-4 and UBC-5 mediate selective degradation of short-lived and abnormal proteins. EMBO J. 9, 543–550.

    Google Scholar 

  • Seufert, W., Futcher, B., Jentsch, S. (1995) Role of ubiquitin conjugating enzyme in degradation of S- and M-phase cyclins. Nature 373, 78–81.

    Google Scholar 

  • St George-Hyslop, P., Haines, J., Rogaev, E., Mortilla, M., Vaula, G., Periak-Vance, M., Foncin, J.F., Montesi, M., Bruni, A., Sorbi, S., Rainero, I., Pinessi, L., Pollen, D., Polinsky, R., Nee, L., Kennedy, J., Macciardi, F., Rogaeva, E., Liang, Y., Alexandrova, N., Lukiw, W., Schlumpf, K., Tanzi, R., Tsuda, T., Farrer, L., Cantu, J.M., Duara, R., Amaducci, L., Bergamini, L., Gusella, J., Roses, A., Mclachlan, D. (1992). Genetic evidence for a novel familial Alzheimer's disease locus on chromosome 14. Nature Genet. 2, 330–334.

    Google Scholar 

  • Treier, M., Seufert, W., Jentsch, S. (1992). Drosophila UbcD1 encodes a highly conserved ubiquitin-conjugating enzyme involved in selective protein degradation. EMBO J. 11, 367–372.

    Google Scholar 

  • Van Broeckhoven, C., Backhovens, H., Cruts, M., De Winter, G., Bruyland, M., Cras, P., Martin, J.J. (1992) Mapping of a gene predisposing to early onset Alzheimer's disease to chromosome 14q24.3. Nature Genet. 2, 335–339.

    Google Scholar 

  • Zhen, M., Heinlein, R., Jones, D., Jentsch, S., Candido, E.P.M. (1993) The ubc-2 gene of Caenorhabditis elegans encodes a ubiquitin-conjugating enzyme involved in selective protein degradation. Mol. Cell. Biol. 13, 1371–1377.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Molecular Medicine Unit, St. James's University Hospital, University of Leeds, Clinical Sciences Building, LS9 7TF, Leeds, UK

    J. P. Leek, I. M. Carr, A. Bailey, T. P. Moynihan, P. L. Coletta, N. J. Lench & A. F. Markham

  2. Leeds Dental Institute, St. James's University Hospital, University of Leeds, Clinical Sciences Building, LS9 7TF, Leeds, UK

    P. A. Robinson & J. Thompson

Authors
  1. P. A. Robinson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. P. Leek
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J. Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. I. M. Carr
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Bailey
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. T. P. Moynihan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. P. L. Coletta
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. N. J. Lench
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A. F. Markham
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Robinson, P.A., Leek, J.P., Thompson, J. et al. A human ubiquitin conjugating enzyme, L-UBC, maps in the Alzheimer's disease locus on Chromosome 14q24.3. Mammalian Genome 6, 725–731 (1995). https://doi.org/10.1007/BF00354295

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00354295

Keywords

Search

Navigation