TAILIEUCHUNG - Báo cáo khoa học: Sugar and alcohol molecules provide a therapeutic strategy for the serpinopathies that cause dementia and cirrhosis

Mutations in neuroserpin anda1-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 a1-antitrypsin-associated cirrhosis. | iFEBS Journal Sugar and alcohol molecules provide a therapeutic strategy for the serpinopathies that cause dementia and cirrhosis Lynda K. Sharp1 z Meera Mallya1 z Kerri J. Kinghorn1 Zhen Wang1 Damian C. Crowther1 James A. Huntington2 Didier Belorgey1 and David A. Lomas1 1 Department of Medicine University of Cambridge UK 2 Department of Haematology University of Cambridge UK Keywords a1-antitrypsin FENIB neuroserpin polymerization serpinopathy Correspondence M. Mallya Department of Medicine University of Cambridge Cambridge Institute for MedicalResearch Wellcome Trust MRC Building Hills Road Cambridge CB2 2XY UK Fax 44 1223 336827 Tel 44 1223 336825 E-mail mm342@ Website http These authors contributed equally to this study. Received 14 February 2006 accepted 5 April 2006 doi Mutations in neuroserpin and a1-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 a1-antitrypsin-associated cirrhosis. Polymers form by a sequential linkage between the reactive centre loop of one molecule and b-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 a1-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 a1-antitrypsin. These data demonstrate that sugar and alcohol molecules can reduce the .

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