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Gene Review

UCHL1  -  ubiquitin carboxyl-terminal esterase L1...

Homo sapiens

Synonyms: HEL-117, NDGOA, Neuron cytoplasmic protein 9.5, PARK5, PGP 9.5, ...
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Disease relevance of UCHL1

  • UCHL1 is a Parkinson's disease susceptibility gene [1].
  • The present finding of an excess of CD45RO/UCHL1 expression in AIDS-related B-cell lymphomas may reflect the preferential expansion of CD45RO expressing B-cell clones with putative autoreactive potential, as suggested by the expansion of CD45RO expressing B-cells in autoimmune disorders [2].
  • In the latter CD45RO/UCHL1 preferentially associated with EMA expression and EBV infection of the tumor clone, but not with CD45RA [2].
  • Seventy six peripheral T cell lymphomas were examined immunohistologically to test their reactivity with a panel of monoclonal antibodies against 11 T cell associated antigens (CD1-8, CD27, UCHL1, and the T cell antigen receptor) [3].
  • Surgical biopsies obtained from 32 children, and 34 adults with Hodgkin's disease (HD) were investigated for the expression of the EBV encoded Latent Membrane Protein 1 (LMP-1), bcl-2 protein, markers for HD; LeuM1 (CD15), BerH2 (CD30) and the new BLA.36, as well as for B (L26) and T lymphocytes (UCHL1) [4].

Psychiatry related information on UCHL1

  • Analysis of functional polymorphisms in three synaptic plasticity-related genes (BDNF, COMT AND UCHL1) in Alzheimer's disease in Colombia [5].
  • The S18Y polymorphism in the UCHL1 gene is a genetic modifier in Huntington's disease [6].
  • These may be silent clinically or present with burning feet, neurovascular abnormalities, wherein warm, cold, and heat pain thresholds are disturbed in association with impairment in skin blood flow and loss of PGP 9.5 immunostaining nerves in the skin [7].

High impact information on UCHL1

  • The assumption that each enzyme expresses a single enzymatic activity in vivo is challenged by the linkage of the neuronal enzyme ubiquitin C-terminal hydrolase-L1 (UCH-L1) to Parkinson's disease (PD) [8].
  • UCH-L1, especially those variants linked to higher susceptibility to PD, causes the accumulation of alpha-synuclein in cultured cells, an effect that cannot be explained by its recognized hydrolase activity [8].
  • The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase [9].
  • Replacement of the threonine residue at position 8 (last amino acid encoded in exon 3 and a putative O-linked carbohydrate anchorage site) by an alanine, completely abrogated the reactivity of the UCHL1 mAb, but did not affect that of the A6 mAb [10].
  • The anti-CD45RO-like A6 mAb, but not the anti-CD45RO UCHL1 mAb, also weakly reacted with transfectant cells expressing the human CD45 isoforms that contained exons 4 and 5(AB), or exon 5(B) encoded sequences [10].

Chemical compound and disease context of UCHL1


Biological context of UCHL1

  • The phenotype of these cells was determined, using dual-color immunofluorescence, to be CD2+, CD3+, CD4+, CD5+, CD7-, CD8-. They do not express T-cell activation markers, and are positive for UCHL1 (CD45RO), but negative for 2H4 (CD45RA) [16].
  • For women only, we observed an epistatic interaction of UCHL1 and alpha-synuclein genotypes with significant effects on PD risk (odds ratio = 2.42; P = 0.003) [17].
  • The gene for human neurone specific ubiquitin C-terminal hydrolase (UCHL1, PGP9.5) maps to chromosome 4p14 [18].
  • We found that homozygosity for the V66M polymorphism of the BDNF gene occurs more frequently in PD patients than in unaffected controls and confirmed an association with the S18Y polymorphism of the UCHL1 gene.We further started microsatellite marker-based genome-wide association studies by using the pooled DNA method [19].
  • Here, we report their purification, physical characteristics, and the mutagenesis of UCH-L1 [20].

Anatomical context of UCHL1

  • In seven cases (4 NS, 2 LP, 1 LD) the monomorphic growths possessed a B-cell phenotype (LCA, L26, and LN1 positive; Leu-M1 and UCHL1 negative) [21].
  • Comparison of EMBs displaying various grades of rejection showed that whereas the absolute number of leukocytes (CD45), memory T cells (UCHL1/CD45RO), helper T cells (OPD4), and macrophages (Mac387) increased with increasing grade of rejection, the proportions of each subset remained similar [22].
  • Other familial PD mutations have identified genes involved in the ubiquitin-proteasome system [parkin and ubiquitin C-terminal hydroxylase L1 (UCHL1)], although such cases do not produce Lewy bodies [23].
  • Expression of the CD45RO putative memory cell antigen on CD4 (helper) and CD8 (cytotoxic/suppressor) lymphocytes of children born to HIV-infected women was investigated using the UCHL1 antibody [24].
  • Among the T-cell markers, UCHL1 and MT1 stained 66% and 50% of the cells, respectively, which could be explained by their cross-reactivity with myeloid cells [25].

Associations of UCHL1 with chemical compounds

  • Our proteomic analyses reveal that the full-length UCH-L1 is a major target of oxidative damage in AD and PD brains, which is extensively modified by carbonyl formation, methionine oxidation, and cysteine oxidation [26].
  • Derangements in parkin function as well as mutations in UCH-L1 fit with the notion that derangements in the ubiquitin proteasomal pathway (UPP) may play important roles in the demise of dopamine neurons in PD [27].
  • Furthermore, we found that oxidation of UCH-L1 by 4-hydroxynonenal, a candidate for endogenous mediator of oxidative stress-induced neuronal cell death, results in a loss of hydrolase activity [28].
  • Conversely, replacement of either the asparagine at position 174 or the serine at position 176 (the first two putative carbohydrate anchorage sites in exon 7) by alanine, abrogated the reactivity of the A6 mAb, but not that of the UCHL1 mAb [10].
  • Fifteen cases of NLNHL involving the thymus were studied by paraffin-section immunohistochemistry using antibodies to formalin-resistant epitopes of B cells (4KB5 [CD45RA] and L26 [CD20]) and T cells (L60 [CD43] and UCHL1 [CD45RO]) [29].

Regulatory relationships of UCHL1

  • Cells of two of ten CD4-positive clones expressed CD45RA (2H4) in addition to UCHL1 [30].
  • The mean densities of NPY and VIP fibres around the intercalated ducts expressed as the percentage of PGP 9.5 fibres associated with these ducts were 52.37 +/- 6.19% and 59.62 +/- 7.02% respectively [31].
  • UCH-L1 was highly expressed in tumor cell lines of epithelial and hematopoietic cell origin but was not detected in freshly isolated and mitogen-activated cells [32].
  • We conclude that the UCH-L1 gene may be a genetic factor that influences the variability in age-at-onset of HD [33].
  • Although the neuronal marker PGP9.5 was coexpressed with nestin at the 14th WOG, this could no longer be observed at later time points [34].

Other interactions of UCHL1


Analytical, diagnostic and therapeutic context of UCHL1


  1. UCHL1 is a Parkinson's disease susceptibility gene. Maraganore, D.M., Lesnick, T.G., Elbaz, A., Chartier-Harlin, M.C., Gasser, T., Krüger, R., Hattori, N., Mellick, G.D., Quattrone, A., Satoh, J., Toda, T., Wang, J., Ioannidis, J.P., de Andrade, M., Rocca, W.A., Toda, T. Ann. Neurol. (2004) [Pubmed]
  2. High frequency of CD45RO expression in AIDS-related B-cell non-Hodgkin's lymphomas. Gloghini, A., De Paoli, P., Gaidano, G., Franceschi, S., Carbone, A. Am. J. Clin. Pathol. (1995) [Pubmed]
  3. Aberrant phenotypes in peripheral T cell lymphomas. Hastrup, N., Ralfkiaer, E., Pallesen, G. J. Clin. Pathol. (1989) [Pubmed]
  4. Expression of EBV encoded latent membrane protein 1 (LMP-1) and bcl-2 protein in childhood and adult Hodgkin's disease: application of microwave irradiation for antigen retrieval. Kaczorowski, S., Kaczorowska, M., Christensson, B. Leuk. Lymphoma (1994) [Pubmed]
  5. Analysis of functional polymorphisms in three synaptic plasticity-related genes (BDNF, COMT AND UCHL1) in Alzheimer's disease in Colombia. Forero, D.A., Benítez, B., Arboleda, G., Yunis, J.J., Pardo, R., Arboleda, H. Neurosci. Res. (2006) [Pubmed]
  6. The S18Y polymorphism in the UCHL1 gene is a genetic modifier in Huntington's disease. Metzger, S., Bauer, P., Tomiuk, J., Laccone, F., Didonato, S., Gellera, C., Soliveri, P., Lange, H.W., Weirich-Schwaiger, H., Wenning, G.K., Melegh, B., Havasi, V., Balikó, L., Wieczorek, S., Arning, L., Zaremba, J., Sulek, A., Hoffman-Zacharska, D., Basak, A.N., Ersoy, N., Zidovska, J., Kebrdlova, V., Pandolfo, M., Ribaï, P., Kadasi, L., Kvasnicova, M., Weber, B.H., Kreuz, F., Dose, M., Stuhrmann, M., Riess, O. Neurogenetics (2006) [Pubmed]
  7. Small fiber neuropathy and neurovascular disturbances in diabetes mellitus. Vinik, A.I., Erbas, T., Stansberry, K.B., Pittenger, G.L. Exp. Clin. Endocrinol. Diabetes (2001) [Pubmed]
  8. The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Liu, Y., Fallon, L., Lashuel, H.A., Liu, Z., Lansbury, P.T. Cell (2002) [Pubmed]
  9. The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase. Wilkinson, K.D., Lee, K.M., Deshpande, S., Duerksen-Hughes, P., Boss, J.M., Pohl, J. Science (1989) [Pubmed]
  10. Identification of amino acids at the junction of exons 3 and 7 that are used for the generation of glycosylation-related human CD45RO and CD45RO-like antigen specificities. Pulido, R., Schlossman, S.F., Saito, H., Streuli, M. J. Exp. Med. (1994) [Pubmed]
  11. Monoclonal antibody (UCHL1) that recognises normal and neoplastic T cells in routinely fixed tissues. Norton, A.J., Ramsay, A.D., Smith, S.H., Beverley, P.C., Isaacson, P.G. J. Clin. Pathol. (1986) [Pubmed]
  12. Alpha-synuclein and parkin contribute to the assembly of ubiquitin lysine 63-linked multiubiquitin chains. Doss-Pepe, E.W., Chen, L., Madura, K. J. Biol. Chem. (2005) [Pubmed]
  13. Analysis of alpha-synuclein, parkin, tau, and UCH-L1 in a Japanese family with autosomal dominant parkinsonism. Hasegawa, K., Funayama, M., Matsuura, N., Furusawa, H., Sakai, F., Kowa, H., Obata, F. Eur. Neurol. (2001) [Pubmed]
  14. Mesotheliomas with deciduoid morphology: a morphologic spectrum and a variant not confined to young females. Shanks, J.H., Harris, M., Banerjee, S.S., Eyden, B.P., Joglekar, V.M., Nicol, A., Hasleton, P.S., Nicholson, A.G. Am. J. Surg. Pathol. (2000) [Pubmed]
  15. Paclitaxel- and vincristine-evoked painful peripheral neuropathies: Loss of epidermal innervation and activation of Langerhans cells. Siau, C., Xiao, W., Bennett, G.J. Exp. Neurol. (2006) [Pubmed]
  16. A new monoclonal antibody (CH-F42) recognizes a CD7- subset of normal T lymphocytes and circulating malignant cells in adult T-cell lymphoma-leukemia and Sézary syndrome. Labastide, W.B., Rana, M.T., Barker, C.R. Blood (1990) [Pubmed]
  17. Complex interactions in Parkinson's disease: a two-phased approach. Maraganore, D.M., de Andrade, M., Lesnick, T.G., Farrer, M.J., Bower, J.H., Hardy, J.A., Rocca, W.A. Mov. Disord. (2003) [Pubmed]
  18. The gene for human neurone specific ubiquitin C-terminal hydrolase (UCHL1, PGP9.5) maps to chromosome 4p14. Edwards, Y.H., Fox, M.F., Povey, S., Hinks, L.J., Thompson, R.J., Day, I.N. Ann. Hum. Genet. (1991) [Pubmed]
  19. Toward identification of susceptibility genes for sporadic Parkinson's disease. Toda, T., Momose, Y., Murata, M., Tamiya, G., Yamamoto, M., Hattori, N., Inoko, H. J. Neurol. (2003) [Pubmed]
  20. Substrate binding and catalysis by ubiquitin C-terminal hydrolases: identification of two active site residues. Larsen, C.N., Price, J.S., Wilkinson, K.D. Biochemistry (1996) [Pubmed]
  21. Monomorphic lymphomas arising in patients with Hodgkin's disease. Correlation of morphologic, immunophenotypic, and molecular genetic findings in 12 cases. Casey, T.T., Cousar, J.B., Mangum, M., Williams, M.E., Lee, J.T., Greer, J.P., Collins, R.D. Am. J. Pathol. (1990) [Pubmed]
  22. Analysis of proliferating cell nuclear antigen expression aids histological diagnosis and is predictive of progression of human cardiac allograft rejection. Salom, R.N., Maguire, J.A., Esmore, D., Hancock, W.W. Am. J. Pathol. (1994) [Pubmed]
  23. Genetic contributions to Parkinson's disease. Huang, Y., Cheung, L., Rowe, D., Halliday, G. Brain Res. Brain Res. Rev. (2004) [Pubmed]
  24. Increased expression of the CD45RO (memory) antigen on T cells in HIV-infected children. Froebel, K.S., Doherty, K.V., Whitelaw, J.A., Hague, R.A., Mok, J.Y., Bird, A.G. AIDS (1991) [Pubmed]
  25. Immunoarchitecture of normal human bone marrow: a study of frozen and fixed tissue sections. Shin, S.S., Sheibani, K., Kezirian, J., Nademanee, A., Forman, S.J., Lee, S.K., Winberg, C.D. Hum. Pathol. (1992) [Pubmed]
  26. Oxidative modifications and down-regulation of ubiquitin carboxyl-terminal hydrolase L1 associated with idiopathic Parkinson's and Alzheimer's diseases. Choi, J., Levey, A.I., Weintraub, S.T., Rees, H.D., Gearing, M., Chin, L.S., Li, L. J. Biol. Chem. (2004) [Pubmed]
  27. New insights into Parkinson's disease. Chung, K.K., Dawson, V.L., Dawson, T.M. J. Neurol. (2003) [Pubmed]
  28. Alterations of structure and hydrolase activity of parkinsonism-associated human ubiquitin carboxyl-terminal hydrolase L1 variants. Nishikawa, K., Li, H., Kawamura, R., Osaka, H., Wang, Y.L., Hara, Y., Hirokawa, T., Manago, Y., Amano, T., Noda, M., Aoki, S., Wada, K. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  29. Primary large-cell lymphoma of the thymus: a diffuse B-cell neoplasm presenting as primary mediastinal lymphoma. Davis, R.E., Dorfman, R.F., Warnke, R.A. Hum. Pathol. (1990) [Pubmed]
  30. Tumor-infiltrating lymphocytes isolated from a Ki-1-positive large cell lymphoma of the skin. Phenotypic characterization and analysis of cytokine secretion. Reinhold, U., Abken, H., Kukel, S., Goeden, B., Uerlich, M., Neumann, U., Kreysel, H.W. Cancer (1991) [Pubmed]
  31. Neuropeptide-containing nerve fibres in the human parotid gland: a semiquantitative analysis using an antibody against protein gene product 9.5. Matsuda, H., Kusakabe, T., Kawakami, T., Nagahara, T., Takenaka, T., Tsukuda, M. Histochem. J. (1997) [Pubmed]
  32. Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells. Ovaa, H., Kessler, B.M., Rolén, U., Galardy, P.J., Ploegh, H.L., Masucci, M.G. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  33. Mutation analysis and association studies of the ubiquitin carboxy-terminal hydrolase L1 gene in Huntington's disease. Nazé, P., Vuillaume, I., Destée, A., Pasquier, F., Sablonnière, B. Neurosci. Lett. (2002) [Pubmed]
  34. Expression of intermediate filament proteins and neuronal markers in the human fetal gut. Rauch, U., Klotz, M., Maas-Omlor, S., Wink, E., Hänsgen, A., Hagl, C., Holland-Cunz, S., Schäfer, K.H. J. Histochem. Cytochem. (2006) [Pubmed]
  35. Interaction and colocalization of PGP9.5 with JAB1 and p27(Kip1). Caballero, O.L., Resto, V., Patturajan, M., Meerzaman, D., Guo, M.Z., Engles, J., Yochem, R., Ratovitski, E., Sidransky, D., Jen, J. Oncogene (2002) [Pubmed]
  36. Molecular findings in familial Parkinson disease in Spain. Hoenicka, J., Vidal, L., Morales, B., Ampuero, I., Jiménez-Jiménez, F.J., Berciano, J., del Ser, T., Jiménez, A., Ruíz, P.G., de Yébenes, J.G. Arch. Neurol. (2002) [Pubmed]
  37. UCH-L1 aggresome formation in response to proteasome impairment indicates a role in inclusion formation in Parkinson's disease. Ardley, H.C., Scott, G.B., Rose, S.A., Tan, N.G., Robinson, P.A. J. Neurochem. (2004) [Pubmed]
  38. Small early gastric cancer with special reference to macrophage infiltration. Caruso, R.A., Vitullo, P., Modesti, A., Inferrera, C. Mod. Pathol. (1999) [Pubmed]
  39. Progress in familial Parkinson's disease. Mizuno, Y., Hattori, N., Yoshino, H., Hatano, Y., Satoh, K., Tomiyama, H., Li, Y. J. Neural Transm. Suppl. (2006) [Pubmed]
  40. Isoform-specific associations of CD45 with accessory molecules in human T lymphocytes. Dianzani, U., Redoglia, V., Malavasi, F., Bragardo, M., Pileri, A., Janeway, C.A., Bottomly, K. Eur. J. Immunol. (1992) [Pubmed]
  41. Granulomatous slack skin: a clinicopathological and immunohistochemical study of three cases. Helm, K.F., Cerio, R., Winkelmann, R.K. Br. J. Dermatol. (1992) [Pubmed]
  42. Ubiquitin C-terminal hydrolase-L1 (PGP9.5) expression in human neural cell lines following induction of neuronal differentiation and exposure to cytokines, neurotrophic factors or heat stress. Satoh, J.I., Kuroda, Y. Neuropathol. Appl. Neurobiol. (2001) [Pubmed]
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