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Familial dementia caused by polymerization of mutant neuroserpin.


Davis, R L; Shrimpton, A E; Holohan, P D; Bradshaw, C; Feiglin, D; Collins, G H; Sonderegger, P; Kinter, J; Becker, L M; Lacbawan, F; Krasnewich, D; Muenke, M; Lawrence, D A; Yerby, M S; Shaw, C M; Gooptu, B; Elliott, P R; Finch, J T; Carrell, R W; Lomas, D A (1999). Familial dementia caused by polymerization of mutant neuroserpin. Nature, 401(6751):376-379.

Abstract

Aberrant protein processing with tissue deposition is associated with many common neurodegenerative disorders; however, the complex interplay of genetic and environmental factors has made it difficult to decipher the sequence of events linking protein aggregation with clinical disease. Substantial progress has been made toward understanding the pathophysiology of prototypical conformational diseases and protein polymerization in the superfamily of serine proteinase inhibitors (serpins). Here we describe a new disease, familial encephalopathy with neuroserpin inclusion bodies, characterized clinically as an autosomal dominantly inherited dementia, histologically by unique neuronal inclusion bodies and biochemically by polymers of the neuron-specific serpin, neuroserpin. We report the cosegregation of point mutations in the neuroserpin gene (PI12) with the disease in two families. The significance of one mutation, S49P, is evident from its homology to a previously described serpin mutations, whereas that of the other, S52R, is predicted by modelling of the serpin template. Our findings provide a molecular mechanism for a familial dementia and imply that inhibitors of protein polymerization may be effective therapies for this disorder and perhaps for other more common neurodegenerative diseases.

Aberrant protein processing with tissue deposition is associated with many common neurodegenerative disorders; however, the complex interplay of genetic and environmental factors has made it difficult to decipher the sequence of events linking protein aggregation with clinical disease. Substantial progress has been made toward understanding the pathophysiology of prototypical conformational diseases and protein polymerization in the superfamily of serine proteinase inhibitors (serpins). Here we describe a new disease, familial encephalopathy with neuroserpin inclusion bodies, characterized clinically as an autosomal dominantly inherited dementia, histologically by unique neuronal inclusion bodies and biochemically by polymers of the neuron-specific serpin, neuroserpin. We report the cosegregation of point mutations in the neuroserpin gene (PI12) with the disease in two families. The significance of one mutation, S49P, is evident from its homology to a previously described serpin mutations, whereas that of the other, S52R, is predicted by modelling of the serpin template. Our findings provide a molecular mechanism for a familial dementia and imply that inhibitors of protein polymerization may be effective therapies for this disorder and perhaps for other more common neurodegenerative diseases.

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233 citations in Web of Science®
259 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Department of Biochemistry
07 Faculty of Science > Department of Biochemistry
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:23 September 1999
Deposited On:11 Feb 2008 12:20
Last Modified:05 Apr 2016 12:17
Publisher:Nature Publishing Group
ISSN:0028-0836
Funders:Pathology Department Medical Service Group, SUNY HSC; Hendricks fund SUNY HSC (A.E.S. and P.D.H); NIH (P.D.H.), Wellcome Trust and Medical Research Council;a CAP Foundation Award (R.L.D.).
Publisher DOI:10.1038/43894
PubMed ID:10517635

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