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Familial dementia caused by polymerization of mutant neuroserpin

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.

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Figure 1: Identification, purification and composition of Collins bodies.
Figure 2: Identification and genotyping of PI12Syracuse mutation.
Figure 3: Electron microscopy of Collins bodies and serpin polymers.
Figure 4: Serpin polymerization.

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Acknowledgements

We thank the Harvard Brain Tissue Resource Center, J. Gusella and R. Myers, Massachusetts General Hospital for three cell lines, and C. Hubbell, C. Lamberson and K. Hicks for technical assistance. This work was supported by the Pathology Department Medical Service Group, SUNY HSC; Hendricks fund SUNY HSC (A.E.S. and P.D.H.); NIH (P.D.H.); the Wellcome Trust and Medical Research Council; and a CAP Foundation Award (R.L.D.).

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Correspondence to Antony E. Shrimpton.

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Davis, R., Shrimpton, A., Holohan, P. et al. Familial dementia caused by polymerization of mutant neuroserpin. Nature 401, 376–379 (1999). https://doi.org/10.1038/43894

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