{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T19:47:30Z","timestamp":1788292050941,"version":"build-2803163510"},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,11,23]],"date-time":"2016-11-23T00:00:00Z","timestamp":1479859200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,11,23]],"date-time":"2016-11-23T00:00:00Z","timestamp":1479859200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Aspartylglucosaminuria (AGU) is a lysosomal storage disorder that is caused by genetic deficiency of the enzyme aspartylglucosaminidase (AGA) which is involved in glycoprotein degradation. AGU is a progressive disorder that results in severe mental retardation in early adulthood. No curative therapy is currently available for AGU. We have here characterized the consequences of a novel AGU mutation that results in Thr122Lys exchange in AGA, and compared this mutant form to one carrying the worldwide most common AGU mutation, AGU-Fin. We show that T122K mutated AGA is expressed in normal amounts and localized in lysosomes, but exhibits low AGA activity due to impaired processing of the precursor molecule into subunits. Coexpression of T122K with wildtype AGA results in processing of the precursor into subunits, implicating that the mutation causes a local misfolding that prevents the precursor from becoming processed. Similar data were obtained for the AGU-Fin mutant polypeptide. We have here also identified small chemical compounds that function as chemical or pharmacological chaperones for the mutant AGA. Treatment of patient fibroblasts with these compounds results in increased AGA activity and processing, implicating that these substances may be suitable for chaperone mediated therapy for AGU.<\/jats:p>","DOI":"10.1038\/srep37583","type":"journal-article","created":{"date-parts":[[2016,11,23]],"date-time":"2016-11-23T10:32:48Z","timestamp":1479897168000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":44,"title":["Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria"],"prefix":"10.1038","volume":"6","author":[{"given":"Antje","family":"Banning","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"G\u00fclec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juha","family":"Rouvinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J.","family":"Gray","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ritva","family":"Tikkanen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,11,23]]},"reference":[{"key":"BFsrep37583_CR1","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1177\/0883073812469049","volume":"29","author":"T Opladen","year":"2014","unstructured":"Opladen, T. et al. Aspartylglucosaminuria: unusual neonatal presentation in Qatari twins with a novel aspartylglucosaminidase gene mutation and 3 new cases in a Turkish family. J Child Neurol 29, 36\u201342 (2014).","journal-title":"J Child Neurol"},{"key":"BFsrep37583_CR2","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1093\/hmg\/10.9.983","volume":"10","author":"J Saarela","year":"2001","unstructured":"Saarela, J. et al. Molecular pathogenesis of a disease: structural consequences of aspartylglucosaminuria mutations. Hum Mol Genet 10, 983\u2013995 (2001).","journal-title":"Hum Mol Genet"},{"key":"BFsrep37583_CR3","doi-asserted-by":"crossref","first-page":"11222","DOI":"10.1073\/pnas.88.24.11222","volume":"88","author":"E Ikonen","year":"1991","unstructured":"Ikonen, E. et al. Spectrum of mutations in aspartylglucosaminuria. Proc Natl Acad Sci USA 88, 11222\u201311226 (1991).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep37583_CR4","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1089\/dna.1995.14.305","volume":"14","author":"R Tikkanen","year":"1995","unstructured":"Tikkanen, R., Enomaa, N., Riikonen, A., Ikonen, E. & Peltonen, L. Intracellular sorting of aspartylglucosaminidase: the role of N-linked oligosaccharides and evidence of Man-6-P-independent lysosomal targeting. DNA Cell Biol 14, 305\u2013312 (1995).","journal-title":"DNA Cell Biol"},{"key":"BFsrep37583_CR5","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1038\/nsb1295-1102","volume":"2","author":"C Oinonen","year":"1995","unstructured":"Oinonen, C., Tikkanen, R., Rouvinen, J. & Peltonen, L. Three-dimensional structure of human lysosomal aspartylglucosaminidase. Nat Struct Biol 2, 1102\u20131108 (1995).","journal-title":"Nat Struct Biol"},{"key":"BFsrep37583_CR6","doi-asserted-by":"crossref","first-page":"2954","DOI":"10.1002\/j.1460-2075.1996.tb00658.x","volume":"15","author":"R Tikkanen","year":"1996","unstructured":"Tikkanen, R., Riikonen, A., Oinonen, C., Rouvinen, R. & Peltonen, L. Functional analyses of active site residues of human lysosomal aspartylglucosaminidase: implications for catalytic mechanism and autocatalytic activation. EMBO J 15, 2954\u20132960 (1996).","journal-title":"EMBO J"},{"key":"BFsrep37583_CR7","doi-asserted-by":"crossref","first-page":"25320","DOI":"10.1074\/jbc.273.39.25320","volume":"273","author":"J Saarela","year":"1998","unstructured":"Saarela, J. et al. Activation and oligomerization of aspartylglucosaminidase. J Biol Chem 273, 25320\u201325328 (1998).","journal-title":"J Biol Chem"},{"key":"BFsrep37583_CR8","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1002\/j.1460-2075.1991.tb07920.x","volume":"10","author":"E Ikonen","year":"1991","unstructured":"Ikonen, E. et al. Aspartylglucosaminuria: cDNA encoding human aspartylglucosaminidase and the missense mutation causing the disease. EMBO J 10, 51\u201358 (1991).","journal-title":"EMBO J"},{"key":"BFsrep37583_CR9","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.1073\/pnas.88.7.2941","volume":"88","author":"I Mononen","year":"1991","unstructured":"Mononen, I. et al. Aspartylglycosaminuria in the Finnish population: identification of two point mutations in the heavy chain of glycoasparaginase. Proc Natl Acad Sci USA 88, 2941\u20132945 (1991).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep37583_CR10","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1007\/s10545-010-9158-7","volume":"33","author":"U Dunder","year":"2010","unstructured":"Dunder, U., Valtonen, P., Kelo, E. & Mononen, I. Early initiation of enzyme replacement therapy improves metabolic correction in the brain tissue of aspartylglycosaminuria mice. J Inherit Metab Dis 33, 611\u2013617 (2010).","journal-title":"J Inherit Metab Dis"},{"key":"BFsrep37583_CR11","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1093\/glycob\/cwh145","volume":"15","author":"E Kelo","year":"2005","unstructured":"Kelo, E., Dunder, U. & Mononen, I. Massive accumulation of Man2GlcNAc2-Asn in nonneuronal tissues of glycosylasparaginase-deficient mice and its removal by enzyme replacement therapy. Glycobiology 15, 79\u201385 (2005).","journal-title":"Glycobiology"},{"key":"BFsrep37583_CR12","doi-asserted-by":"crossref","first-page":"1314","DOI":"10.1038\/sj.gt.3300740","volume":"5","author":"M Peltola","year":"1998","unstructured":"Peltola, M. et al. Adenovirus-mediated gene transfer results in decreased lysosomal storage in brain and total correction in liver of aspartylglucosaminuria (AGU) mouse. Gene Ther 5, 1314\u20131321 (1998).","journal-title":"Gene Ther"},{"key":"BFsrep37583_CR13","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1002\/jgm.892","volume":"8","author":"S Virta","year":"2006","unstructured":"Virta, S., Rapola, J., Jalanko, A. & Laine, M. Use of nonviral promoters in adenovirus-mediated gene therapy: reduction of lysosomal storage in the aspartylglucosaminuria mouse. J Gene Med 8, 699\u2013706 (2006).","journal-title":"J Gene Med"},{"key":"BFsrep37583_CR14","doi-asserted-by":"crossref","first-page":"2705","DOI":"10.1021\/jm301557k","volume":"56","author":"RE Boyd","year":"2013","unstructured":"Boyd, R. E. et al. Pharmacological chaperones as therapeutics for lysosomal storage diseases. J Med Chem 56, 2705\u20132725 (2013).","journal-title":"J Med Chem"},{"key":"BFsrep37583_CR15","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1002\/emmm.200900036","volume":"1","author":"G Parenti","year":"2009","unstructured":"Parenti, G. Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics. EMBO Mol Med 1, 268\u2013279 (2009).","journal-title":"EMBO Mol Med"},{"key":"BFsrep37583_CR16","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1146\/annurev-med-122313-085916","volume":"66","author":"G Parenti","year":"2015","unstructured":"Parenti, G., Andria, G. & Ballabio, A. Lysosomal storage diseases: from pathophysiology to therapy. Annu Rev Med 66, 471\u2013486 (2015).","journal-title":"Annu Rev Med"},{"key":"BFsrep37583_CR17","doi-asserted-by":"crossref","first-page":"1677","DOI":"10.1016\/j.bbapap.2006.08.012","volume":"1764","author":"T Arakawa","year":"2006","unstructured":"Arakawa, T., Ejima, D., Kita, Y. & Tsumoto, K. Small molecule pharmacological chaperones: From thermodynamic stabilization to pharmaceutical drugs. Biochim Biophys Acta 1764, 1677\u20131687 (2006).","journal-title":"Biochim Biophys Acta"},{"key":"BFsrep37583_CR18","first-page":"4962","volume":"274","author":"JQ Fan","year":"2007","unstructured":"Fan, J. Q. & Ishii, S. Active-site-specific chaperone therapy for Fabry disease. Yin and Yang of enzyme inhibitors. FEBS J 274, 4962\u20134971 (2007).","journal-title":"Yin and Yang of enzyme inhibitors. FEBS J"},{"key":"BFsrep37583_CR19","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/0888-7543(91)90120-4","volume":"11","author":"E Ikonen","year":"1991","unstructured":"Ikonen, E., Enomaa, N., Ulmanen, I. & Peltonen, L. In vitro mutagenesis helps to unravel the biological consequences of aspartylglucosaminuria mutation. Genomics 11, 206\u2013211 (1991).","journal-title":"Genomics"},{"key":"BFsrep37583_CR20","doi-asserted-by":"crossref","first-page":"21340","DOI":"10.1074\/jbc.271.35.21340","volume":"271","author":"A Riikonen","year":"1996","unstructured":"Riikonen, A. et al. Primary folding of aspartylglucosaminidase. Significance of disulfide bridges and evidence of early multimerization. J Biol Chem 271, 21340\u201321344 (1996).","journal-title":"J Biol Chem"},{"key":"BFsrep37583_CR21","doi-asserted-by":"crossref","first-page":"6684","DOI":"10.1093\/emboj\/16.22.6684","volume":"16","author":"R Tikkanen","year":"1997","unstructured":"Tikkanen, R., Peltola, M., Oinonen, C., Rouvinen, J. & Peltonen, L. Several cooperating binding sites mediate the interaction of a lysosomal enzyme with phosphotransferase. EMBO J 16, 6684\u20136693 (1997).","journal-title":"EMBO J"},{"key":"BFsrep37583_CR22","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.4155\/fmc.14.40","volume":"6","author":"G Parenti","year":"2014","unstructured":"Parenti, G., Moracci, M., Fecarotta, S. & Andria, G. Pharmacological chaperone therapy for lysosomal storage diseases. Future Med Chem 6, 1031\u20131045 (2014).","journal-title":"Future Med Chem"},{"key":"BFsrep37583_CR23","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1055\/s-2007-973506","volume":"30","author":"T Autti","year":"1999","unstructured":"Autti, T. et al. Bone marrow transplantation in aspartylglucosaminuria\u2013histopathological and MRI study. Neuropediatrics 30, 283\u2013288 (1999).","journal-title":"Neuropediatrics"},{"key":"BFsrep37583_CR24","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1111\/j.1399-0004.1997.tb02448.x","volume":"51","author":"A Laitinen","year":"1997","unstructured":"Laitinen, A. et al. Two novel mutations in a Canadian family with aspartylglucosaminuria and early outcome post bone marrow transplantation. Clin Genet 51, 174\u2013178 (1997).","journal-title":"Clin Genet"},{"key":"BFsrep37583_CR25","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1093\/hmg\/7.2.265","volume":"7","author":"A Jalanko","year":"1998","unstructured":"Jalanko, A. et al. Mice with an aspartylglucosaminuria mutation similar to humans replicate the pathophysiology in patients. Hum Mol Genet 7, 265\u2013272 (1998).","journal-title":"Hum Mol Genet"},{"key":"BFsrep37583_CR26","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1038\/nm1296-1375","volume":"2","author":"V Kaartinen","year":"1996","unstructured":"Kaartinen, V. et al. A mouse model for the human lysosomal disease aspartylglycosaminuria. Nat Med 2, 1375\u20131378 (1996).","journal-title":"Nat Med"},{"key":"BFsrep37583_CR27","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.neuropharm.2012.06.024","volume":"68","author":"SJ Gray","year":"2013","unstructured":"Gray, S. J. Gene therapy and neurodevelopmental disorders. Neuropharmacology 68, 136\u2013142 (2013).","journal-title":"Neuropharmacology"},{"key":"BFsrep37583_CR28","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1089\/dna.1994.13.257","volume":"13","author":"A Riikonen","year":"1994","unstructured":"Riikonen, A. et al. Dissection of the molecular consequences of a double mutation causing a human lysosomal disease. DNA Cell Biol 13, 257\u2013264 (1994).","journal-title":"DNA Cell Biol"},{"key":"BFsrep37583_CR29","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1016\/j.str.2014.09.014","volume":"22","author":"L Sui","year":"2014","unstructured":"Sui, L., Lakshminarasimhan, D., Pande, S. & Guo, H. C. Structural basis of a point mutation that causes the genetic disease aspartylglucosaminuria. Structure 22, 1855\u20131861 (2014).","journal-title":"Structure"},{"key":"BFsrep37583_CR30","doi-asserted-by":"crossref","first-page":"3210","DOI":"10.1074\/jbc.M210431200","volume":"278","author":"Y Wang","year":"2003","unstructured":"Wang, Y. & Guo, H. C. Two-step dimerization for autoproteolysis to activate glycosylasparaginase. J Biol Chem 278, 3210\u20133219 (2003).","journal-title":"J Biol Chem"},{"key":"BFsrep37583_CR31","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1074\/jbc.271.3.1732","volume":"271","author":"C Guan","year":"1996","unstructured":"Guan, C. et al. Activation of glycosylasparaginase. Formation of active N-terminal threonine by intramolecular autoproteolysis. J Biol Chem 271, 1732\u20131737 (1996).","journal-title":"J Biol Chem"},{"key":"BFsrep37583_CR32","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1080\/14756360109162375","volume":"16","author":"JM Risley","year":"2001","unstructured":"Risley, J. M., Huang, D. H., Kaylor, J. J., Malik, J. J. & Xia, Y. Q. Glycosylasparaginase inhibition studies: competitive inhibitors, transition state mimics, noncompetitive inhibitors. J Enzyme Inhib 16, 269\u2013274 (2001).","journal-title":"J Enzyme Inhib"},{"key":"BFsrep37583_CR33","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1016\/S0092-8674(00)80052-5","volume":"98","author":"Q Xu","year":"1999","unstructured":"Xu, Q., Buckley, D., Guan, C. & Guo, H. C. Structural insights into the mechanism of intramolecular proteolysis. Cell 98, 651\u2013661 (1999).","journal-title":"Cell"},{"key":"BFsrep37583_CR34","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1016\/j.chembiol.2013.03.006","volume":"20","author":"Y Su","year":"2013","unstructured":"Su, Y. et al. Free glycine accelerates the autoproteolytic activation of human asparaginase. Chem Biol 20, 533\u2013540 (2013).","journal-title":"Chem Biol"},{"key":"BFsrep37583_CR35","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1093\/ajcn\/80.3.539","volume":"80","author":"SA Craig","year":"2004","unstructured":"Craig, S. A. Betaine in human nutrition. Am J Clin Nutr 80, 539\u2013549 (2004).","journal-title":"Am J Clin Nutr"},{"key":"BFsrep37583_CR36","doi-asserted-by":"crossref","first-page":"5569","DOI":"10.1073\/pnas.0914960107","volume":"107","author":"R Zhang","year":"2010","unstructured":"Zhang, R. et al. Recovery of PEX1-Gly843Asp peroxisome dysfunction by small-molecule compounds. Proc Natl Acad Sci USA 107, 5569\u20135574 (2010).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep37583_CR37","doi-asserted-by":"crossref","first-page":"7277","DOI":"10.1073\/pnas.1131968100","volume":"100","author":"A Santana","year":"2003","unstructured":"Santana, A., Salido, E., Torres, A. & Shapiro, L. J. Primary hyperoxaluria type 1 in the Canary Islands: a conformational disease due to I244T mutation in the P11L-containing alanine:glyoxylate aminotransferase. Proc Natl Acad Sci USA 100, 7277\u20137282 (2003).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep37583_CR38","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1023\/B:BOLI.0000042959.44318.7c","volume":"27","author":"UH Schueler","year":"2004","unstructured":"Schueler, U. H. et al. Correlation between enzyme activity and substrate storage in a cell culture model system for Gaucher disease. J Inherit Metab Dis 27, 649\u2013658 (2004).","journal-title":"J Inherit Metab Dis"},{"key":"BFsrep37583_CR39","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1089\/hum.2012.107","volume":"24","author":"S Mussche","year":"2013","unstructured":"Mussche, S. et al. Restoration of cytoskeleton homeostasis after gigaxonin gene transfer for giant axonal neuropathy. Hum Gene Ther 24, 209\u2013219 (2013).","journal-title":"Hum Gene Ther"},{"key":"BFsrep37583_CR40","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1034\/j.1600-0854.2000.010807.x","volume":"1","author":"R Tikkanen","year":"2000","unstructured":"Tikkanen, R. et al. The dileucine motif within the tail of MPR46 is required for sorting of the receptor in endosomes. Traffic 1, 631\u2013640 (2000).","journal-title":"Traffic"},{"key":"BFsrep37583_CR41","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1007\/BF00711507","volume":"16","author":"Ya,V Voznyi","year":"1993","unstructured":"Voznyi Ya, V. et al. Applications of a new fluorimetric enzyme assay for the diagnosis of aspartylglucosaminuria. J Inherit Metab Dis 16, 929\u2013934 (1993).","journal-title":"J Inherit Metab Dis"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep37583.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep37583","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep37583.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T02:19:33Z","timestamp":1672885173000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep37583"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,23]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,23]]}},"alternative-id":["BFsrep37583"],"URL":"https:\/\/doi.org\/10.1038\/srep37583","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,23]]},"assertion":[{"value":"15 August 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 November 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 November 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"37583"}}