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Sugar and alcohol molecules provide a therapeutic strategy for the serpinopathies that cause dementia and cirrhosis
Author(s) -
Sharp Lynda K.,
Mallya Meera,
Kinghorn Kerri J.,
Wang Zhen,
Crowther Damian C.,
Huntington James A.,
Belorgey Didier,
Lomas David A.
Publication year - 2006
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2006.05262.x
Subject(s) - dementia , sugar , alcohol , cirrhosis , medicine , intensive care medicine , chemistry , biochemistry , disease
Mutations in neuroserpin and α 1 ‐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 α 1 ‐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 α 1 ‐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 α 1 ‐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.