title: Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria.
abstract: 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.
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Banning
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Gülec
authors.affiliation: Department of Chemistry, University of Eastern Finland, PO BOX 111, 80101 Joensuu, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Rouvinen
authors.affiliation: Gene Therapy Center and Department of Ophthalmology, University of North Carolina, Chapel Hill, NC 27302, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Gray
authors.affiliation: Institute of Biochemistry, Medical Faculty, University of Giessen, Friedrichstrasse 24, 35392 Giessen, Germany.
authors.forename: Ritva
authors.initials: R
authors.lastname: Tikkanen
mesh_terms: D000595:Amino Acid Sequence; D054880:Aspartylglucosaminuria / Q000188:drug therapy* / Q000201:enzymology; D001227:Aspartylglucosylaminase / Q000737:chemistry / Q000235:genetics; D001483:Base Sequence; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018832:Molecular Chaperones / Q000494:pharmacology / Q000627:therapeutic use*; D050505:Mutant Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D054852:Small Molecule Libraries / Q000032:analysis* / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D018832:Molecular Chaperones; D050505:Mutant Proteins; D054852:Small Molecule Libraries; D001227:Aspartylglucosylaminase