Association between conformational mutations in neuroserpin and onset and severity of dementia.
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.
Davis
Richard L
RL
Department of Pathology, Upstate Medical University, Syracuse, NY, USA.
Shrimpton
Antony E
AE
Carrell
Robin W
RW
Lomas
David A
DA
Gerhard
Lieselotte
L
Baumann
Bruno
B
Lawrence
Daniel A
DA
Yepes
Manuel
M
Kim
Tai Seung
TS
Ghetti
Bernardino
B
Piccardo
Pedro
P
Takao
Masaki
M
Lacbawan
Felicitas
F
Muenke
Maximilian
M
Sifers
Richard N
RN
Bradshaw
Charles B
CB
Kent
Paul F
PF
Collins
George H
GH
Larocca
Daria
D
Holohan
Peter D
PD
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
D009479:Neuropeptides; D015843:Serpins; D000097522:Neuroserpin