Association between conformational mutations in neuroserpin and onset and severity of dementia

Richard L. Davis, Antony E. Shrimpton, Robin W. Carrell, David A. Lomas, Lieselotte Gerhard, Bruno Baumann, Daniel A. Lawrence, Manuel Yepes, Tai Seung Kim, Bernardino Ghetti, Pedro Piccardo, Masaki Takao, Felicitas Lacbawan, Maximilian Muenke, Richard N. Sifers, Charles B. Bradshaw, Paul F. Kent, George H. Collins, Daria Larocca, Peter D. Holohan

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

Background: The aggregation of specific proteins is a common feature of the familial dementias, but whether the formation of neuronal inclusion bodies is a causative or incidental factor in the disease is not known. To clarify this issue, we investigated five families with typical neuroserpin inclusion bodies but with various neurological manifestations. Methods: Five families with neurodegenerative disease and typical neuronal inclusions had biopsy or autopsy material available for further examination. Immunostaining confirmed that the inclusions were formed of neuroserpin aggregates, and the responsible mutations in neuroserpin were identified by sequencing of the neuroserpin gene (SERPINI1) in DNA from blood samples or from extraction of histology specimens. Molecular modelling techniques were used to predict the effect of the gene mutations on three-dimensional protein structure. Brain sections were stained and the topographic distribution of the neuroserpin inclusions plotted. Findings: Each of the families was heterozygous for an aminoacid substitution that affected the conformational stability of neuroserpin. The least disruptive of these mutations (S49P), as predicted by molecular modelling, resulted in dementia after age 45 years, and presence of neuroserpin inclusions in only a few neurons. By contrast, the most severely disruptive mutation (G392E) resulted, at age 13 years, in progressive myoclonus epilepsy, with many inclusions present in almost all neurons. Interpretation: The findings provide evidence that inclusion-body formation is in itself a sufficient cause of neurodegeneration, and that the onset and severity of the disease is associated with the rate and magnitude of neuronal protein aggregation.

Original languageEnglish
Pages (from-to)2242-2247
Number of pages6
JournalThe Lancet
Volume359
Issue number9325
DOIs
StatePublished - Jun 29 2002

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Dementia
Mutation
Inclusion Bodies
Progressive Myoclonic Epilepsy
Neurons
Proteins
Neurologic Manifestations
neuroserpin
Neurodegenerative Diseases
Genes
Autopsy
Histology
Biopsy
DNA
Brain

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Davis, R. L., Shrimpton, A. E., Carrell, R. W., Lomas, D. A., Gerhard, L., Baumann, B., ... Holohan, P. D. (2002). Association between conformational mutations in neuroserpin and onset and severity of dementia. The Lancet, 359(9325), 2242-2247. https://doi.org/10.1016/S0140-6736(02)09293-0

Association between conformational mutations in neuroserpin and onset and severity of dementia. / Davis, Richard L.; Shrimpton, Antony E.; Carrell, Robin W.; Lomas, David A.; Gerhard, Lieselotte; Baumann, Bruno; Lawrence, Daniel A.; Yepes, Manuel; Kim, Tai Seung; Ghetti, Bernardino; Piccardo, Pedro; Takao, Masaki; Lacbawan, Felicitas; Muenke, Maximilian; Sifers, Richard N.; Bradshaw, Charles B.; Kent, Paul F.; Collins, George H.; Larocca, Daria; Holohan, Peter D.

In: The Lancet, Vol. 359, No. 9325, 29.06.2002, p. 2242-2247.

Research output: Contribution to journalArticle

Davis, RL, Shrimpton, AE, Carrell, RW, Lomas, DA, Gerhard, L, Baumann, B, Lawrence, DA, Yepes, M, Kim, TS, Ghetti, B, Piccardo, P, Takao, M, Lacbawan, F, Muenke, M, Sifers, RN, Bradshaw, CB, Kent, PF, Collins, GH, Larocca, D & Holohan, PD 2002, 'Association between conformational mutations in neuroserpin and onset and severity of dementia', The Lancet, vol. 359, no. 9325, pp. 2242-2247. https://doi.org/10.1016/S0140-6736(02)09293-0
Davis RL, Shrimpton AE, Carrell RW, Lomas DA, Gerhard L, Baumann B et al. Association between conformational mutations in neuroserpin and onset and severity of dementia. The Lancet. 2002 Jun 29;359(9325):2242-2247. https://doi.org/10.1016/S0140-6736(02)09293-0
Davis, Richard L. ; Shrimpton, Antony E. ; Carrell, Robin W. ; Lomas, David A. ; Gerhard, Lieselotte ; Baumann, Bruno ; Lawrence, Daniel A. ; Yepes, Manuel ; Kim, Tai Seung ; Ghetti, Bernardino ; Piccardo, Pedro ; Takao, Masaki ; Lacbawan, Felicitas ; Muenke, Maximilian ; Sifers, Richard N. ; Bradshaw, Charles B. ; Kent, Paul F. ; Collins, George H. ; Larocca, Daria ; Holohan, Peter D. / Association between conformational mutations in neuroserpin and onset and severity of dementia. In: The Lancet. 2002 ; Vol. 359, No. 9325. pp. 2242-2247.
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AU - Lawrence, Daniel A.

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AU - Piccardo, Pedro

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AU - Muenke, Maximilian

AU - Sifers, Richard N.

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