Sugar and alcohol molecules provide a therapeutic strategy for the serpinopathies that cause dementia and cirrhosis

• Published in: The FEBS journal Vol. 273; no. 11; pp. 2450 - 2552
• Main Authors: Sharp, Lynda K., Mallya, Meera, Kinghorn, Kerri J., Wang, Zhen, Crowther, Damian C., Huntington, James A., Belorgey, Didier, Lomas, David A.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.2006
• Subjects: Alcohol; alpha 1-Antitrypsin - chemistry; alpha 1-Antitrypsin - drug effects; Carbohydrates - therapeutic use; Circular Dichroism; Dementia; Dementia - drug therapy; Erythritol - pharmacology; Ethanol - therapeutic use; FENIB; Glucose - pharmacology; Glycerol - pharmacology; Liver cirrhosis; Liver Cirrhosis - drug therapy; Models, Molecular; Mutation; Neuropeptides - drug effects; Neuropeptides - metabolism; Neuroserpin; Polymerization; Protein Conformation; Protein Structure, Secondary; Recombinant Proteins - drug effects; Recombinant Proteins - metabolism; serpinopathy; Serpins - drug effects; Serpins - metabolism; Sugar; Trehalose - pharmacology; α1‐antitrypsin
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/j.1742-4658.2006.05262.x

Mutations in neuroserpin and α1‐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 α1‐antitrypsin‐associated cirrhosis. Polymers form by a sequential linkage between the reactive centre loop of one molecule and β‐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 α1‐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 α1‐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 β‐sheet A.