Familial dementia caused by polymerization of mutant neuroserpin

R.L. Davis; A.E. Shrimpton; P.D. Holohan; C. Bradshaw; D. Feiglin; G.H. Collins; P. Sonderegger; J. Kinter; L.M. Becker; F. Lacbawan; D. Krasnewich; M. Muenke; D.A. Lawrence; M.S. Yerby; C.-M. Shaw; Bibekbrata Gooptu; P.R. Elliott; J.T. Finch; R.W. Carrell; D.A. Lomas

doi:10.1038/43897

Familial dementia caused by polymerization of mutant neuroserpin

R.L. Davis, A.E. Shrimpton, P.D. Holohan, C. Bradshaw, D. Feiglin, G.H. Collins, P. Sonderegger, J. Kinter, L.M. Becker, F. Lacbawan, D. Krasnewich, M. Muenke, D.A. Lawrence, M.S. Yerby, C.-M. Shaw, Bibekbrata Gooptu, P.R. Elliott, J.T. Finch, R.W. Carrell, D.A. Lomas

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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 neuronspecific 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 mutation, 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.

Original language	English
Pages (from-to)	376-379
Number of pages	4
Journal	NATURE
Volume	401
Issue number	6751
DOIs	https://doi.org/10.1038/43897
Publication status	Published - 23 Sept 1999

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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. https://doi.org/10.1038/43897

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title = "Familial dementia caused by polymerization of mutant neuroserpin",

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 neuronspecific 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 mutation, 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.",

author = "R.L. Davis and A.E. Shrimpton and P.D. Holohan and C. Bradshaw and D. Feiglin and G.H. Collins and P. Sonderegger and J. Kinter and L.M. Becker and F. Lacbawan and D. Krasnewich and M. Muenke and D.A. Lawrence and M.S. Yerby and C.-M. Shaw and Bibekbrata Gooptu and P.R. Elliott and J.T. Finch and R.W. Carrell and D.A. Lomas",

year = "1999",

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Davis, RL, Shrimpton, AE, Holohan, PD, Bradshaw, C, Feiglin, D, Collins, GH, Sonderegger, P, Kinter, J, Becker, LM, Lacbawan, F, Krasnewich, D, Muenke, M, Lawrence, DA, Yerby, MS, Shaw, C-M, Gooptu, B, Elliott, PR, Finch, JT, Carrell, RW & Lomas, DA 1999, 'Familial dementia caused by polymerization of mutant neuroserpin', NATURE, vol. 401, no. 6751, pp. 376-379. https://doi.org/10.1038/43897

TY - JOUR

T1 - Familial dementia caused by polymerization of mutant neuroserpin

AU - Davis, R.L.

AU - Shrimpton, A.E.

AU - Holohan, P.D.

AU - Bradshaw, C.

AU - Feiglin, D.

AU - Collins, G.H.

AU - Sonderegger, P.

AU - Kinter, J.

AU - Becker, L.M.

AU - Lacbawan, F.

AU - Krasnewich, D.

AU - Muenke, M.

AU - Lawrence, D.A.

AU - Yerby, M.S.

AU - Shaw, C.-M.

AU - Gooptu, Bibekbrata

AU - Elliott, P.R.

AU - Finch, J.T.

AU - Carrell, R.W.

AU - Lomas, D.A.

PY - 1999/9/23

Y1 - 1999/9/23

N2 - 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 neuronspecific 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 mutation, 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.

AB - 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 neuronspecific 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 mutation, 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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Familial dementia caused by polymerization of mutant neuroserpin

Abstract

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