title: Association between conformational mutations in neuroserpin and onset and severity of dementia.
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.
  
  
  RESULTS
  Each of the families was heterozygous for an amino acid 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pathology, Upstate Medical University, Syracuse, NY, USA.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Davis
authors.forename: Antony E
authors.initials: AE
authors.lastname: Shrimpton
authors.forename: Robin W
authors.initials: RW
authors.lastname: Carrell
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Lieselotte
authors.initials: L
authors.lastname: Gerhard
authors.forename: Bruno
authors.initials: B
authors.lastname: Baumann
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Lawrence
authors.forename: Manuel
authors.initials: M
authors.lastname: Yepes
authors.forename: Tai Seung
authors.initials: TS
authors.lastname: Kim
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: Pedro
authors.initials: P
authors.lastname: Piccardo
authors.forename: Masaki
authors.initials: M
authors.lastname: Takao
authors.forename: Felicitas
authors.initials: F
authors.lastname: Lacbawan
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenke
authors.forename: Richard N
authors.initials: RN
authors.lastname: Sifers
authors.forename: Charles B
authors.initials: CB
authors.lastname: Bradshaw
authors.forename: Paul F
authors.initials: PF
authors.lastname: Kent
authors.forename: George H
authors.initials: GH
authors.lastname: Collins
authors.forename: Daria
authors.initials: D
authors.lastname: Larocca
authors.forename: Peter D
authors.initials: PD
authors.lastname: Holohan
mesh_terms: D000293:Adolescent; D000328:Adult; D001921:Brain / Q000473:pathology; D003704:Dementia / Q000145:classification / Q000235:genetics*; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009479:Neuropeptides / Q000235:genetics*; D016133:Polymerase Chain Reaction; D015843:Serpins / Q000235:genetics*; D012720:Severity of Illness Index; D000097522:Neuroserpin
chemical_list: D009479:Neuropeptides; D015843:Serpins; D000097522:Neuroserpin