title: Sugar and alcohol molecules provide a therapeutic strategy for the serpinopathies that cause dementia and cirrhosis.
abstract: Mutations in neuroserpin and alpha1-antitrypsin cause these proteins to form ordered polymers that are retained within the endoplasmic reticulum of neurones and hepatocytes, respectively. The resulting inclusions underlie the dementia familial encephalopathy with neuroserpin inclusion bodies (FENIB) and Z alpha1-antitrypsin-associated cirrhosis. Polymers form by a sequential linkage between the reactive centre loop of one molecule and beta-sheet A of another, and strategies that block polymer formation are likely to be successful in treating the associated disease. We show here that glycerol, the sugar alcohol erythritol, the disaccharide trehalose and its breakdown product glucose reduce the rate of polymerization of wild-type neuroserpin and the Ser49Pro mutant that causes dementia. They also attenuate the polymerization of the Z variant of alpha1-antitrypsin. The effect on polymerization was apparent even when these agents had been removed from the buffer. None of these agents had any detectable effect on the structure or inhibitory activity of neuroserpin or alpha1-antitrypsin. These data demonstrate that sugar and alcohol molecules can reduce the polymerization of serpin mutants that cause disease, possibly by binding to and stabilizing beta-sheet A.
authors.affiliation: Department of Medicine, University of Cambridge, UK.
authors.forename: Lynda K
authors.initials: LK
authors.lastname: Sharp
authors.forename: Meera
authors.initials: M
authors.lastname: Mallya
authors.forename: Kerri J
authors.initials: KJ
authors.lastname: Kinghorn
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.forename: Damian C
authors.initials: DC
authors.lastname: Crowther
authors.forename: James A
authors.initials: JA
authors.lastname: Huntington
authors.forename: Didier
authors.initials: D
authors.lastname: Belorgey
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
mesh_terms: D002241:Carbohydrates / Q000627:therapeutic use*; D002942:Circular Dichroism; D003704:Dementia / Q000188:drug therapy*; D004896:Erythritol / Q000494:pharmacology; D000431:Ethanol / Q000627:therapeutic use*; D005947:Glucose / Q000494:pharmacology; D005990:Glycerol / Q000494:pharmacology; D008103:Liver Cirrhosis / Q000188:drug therapy*; D008958:Models, Molecular; D009479:Neuropeptides / Q000187:drug effects / Q000378:metabolism; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000187:drug effects / Q000378:metabolism; D015843:Serpins / Q000187:drug effects / Q000378:metabolism*; D014199:Trehalose / Q000494:pharmacology; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000187:drug effects; D000097522:Neuroserpin
chemical_list: D002241:Carbohydrates; D004896:Erythritol; D000431:Ethanol; D005947:Glucose; D005990:Glycerol; D009479:Neuropeptides; D011994:Recombinant Proteins; D015843:Serpins; D014199:Trehalose; D000515:alpha 1-Antitrypsin; D000097522:Neuroserpin