Familial dementia caused by polymerization of mutant neuroserpin

Richard L. Davis, Antony E. Shrimpton (), Peter D. Holohan, Charles Bradshaw, David Feiglin, George H. Collins, Peter Sonderegger, Jochen Kinter, Lyn Marie Becker, Felicitas Lacbawan, Donna Krasnewich, Maximilian Muenke, Daniel A. Lawrence, Mark S. Yerby, Cheng-Mei Shaw, Bibek Gooptu, Peter R. Elliott, John T. Finch, Robin W. Carrell and David A. Lomas
Additional contact information
Richard L. Davis: Departments of Clinical Pathology
Antony E. Shrimpton: Departments of Clinical Pathology
Peter D. Holohan: Pharmacology
Charles Bradshaw: Neurology
David Feiglin: Radiology, State University of New York Health Science, Center
George H. Collins: Departments of Clinical Pathology
Peter Sonderegger: University of Zurich
Felicitas Lacbawan: National Human Genome Research Institute, National Institutes of Health
Donna Krasnewich: National Human Genome Research Institute, National Institutes of Health
Maximilian Muenke: National Human Genome Research Institute, National Institutes of Health
Daniel A. Lawrence: American Red Cross, Holland Laboratories
Mark S. Yerby: Public Health and Obstetrics-Gynecology, Oregon Health Sciences University
Cheng-Mei Shaw: University of Washington, School of Medicine
Bibek Gooptu: University of Cambridge, Cambridge Institute for Medical Research
Peter R. Elliott: University of Cambridge, Cambridge Institute for Medical Research
John T. Finch: Laboratory of Molecular Biology, MRC Centre
Robin W. Carrell: University of Cambridge, Cambridge Institute for Medical Research
David A. Lomas: University of Cambridge, Cambridge Institute for Medical Research

Nature, 1999, vol. 401, issue 6751, 376-379

Abstract: Abstract 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.

Date: 1999
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DOI: 10.1038/43894

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