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    Familial dementia caused by polymerization of mutant neuroserpin

    Davis, R.L. and Shrimpton, A.E. and Holohan, P.D. and Bradshaw, C. and Feiglin, D. and Collins, G.H. and Sonderegger, P. and Kinter, J. and Becker, L.M. and Lacbawan, F. and Krasnewich, D. and Muenke, M. and Lawrence, D.A. and Yerby, M.S. and Shaw, C.-M. and Gooptu, Bibek and Elliott, P.R. and Finch, J.T. and Carrell, R.W. and Lomas, D.A. (1999) Familial dementia caused by polymerization of mutant neuroserpin. Nature 401 , pp. 376-379. ISSN 0028-0836.

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    Aberrant protein processing with tissue deposition is associated with many common neurodegenerative disorders1, 2; however, the complex interplay of genetic and environmental factors has made it difficult to decipher the sequence of events linking protein aggregation with clinical disease3. Substantial progress has been made toward understanding the pathophysiology of prototypical conformational diseases and protein polymerization in the superfamily of serine proteinase inhibitors (serpins)4, 5. 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, neuroserpin6, 7. 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 mutation8, 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.


    Item Type: Article
    School: Birkbeck Faculties and Schools > Faculty of Science > School of Natural Sciences
    Research Centres and Institutes: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 24 Jun 2015 14:12
    Last Modified: 02 Aug 2023 17:17


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