PMID- 10517635
OWN - NLM
STAT- MEDLINE
DCOM- 19991019
LR  - 20131121
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 401
IP  - 6751
DP  - 1999 Sep 23
TI  - Familial dementia caused by polymerization of mutant neuroserpin.
PG  - 376-9
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 neuron-specific 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 mutations, 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.
FAU - Davis, R L
AU  - Davis RL
AD  - Department of Clinical Pathology, State University of New York Health Science
      Center, Syracuse 13210, USA.
FAU - Shrimpton, A E
AU  - Shrimpton AE
FAU - Holohan, P D
AU  - Holohan PD
FAU - Bradshaw, C
AU  - Bradshaw C
FAU - Feiglin, D
AU  - Feiglin D
FAU - Collins, G H
AU  - Collins GH
FAU - Sonderegger, P
AU  - Sonderegger P
FAU - Kinter, J
AU  - Kinter J
FAU - Becker, L M
AU  - Becker LM
FAU - Lacbawan, F
AU  - Lacbawan F
FAU - Krasnewich, D
AU  - Krasnewich D
FAU - Muenke, M
AU  - Muenke M
FAU - Lawrence, D A
AU  - Lawrence DA
FAU - Yerby, M S
AU  - Yerby MS
FAU - Shaw, C M
AU  - Shaw CM
FAU - Gooptu, B
AU  - Gooptu B
FAU - Elliott, P R
AU  - Elliott PR
FAU - Finch, J T
AU  - Finch JT
FAU - Carrell, R W
AU  - Carrell RW
FAU - Lomas, D A
AU  - Lomas DA
LA  - eng
GR  - Wellcome Trust/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Biopolymers)
RN  - 0 (Neuropeptides)
RN  - 0 (Serpins)
RN  - 0 (neuroserpin)
RN  - 452VLY9402 (Serine)
RN  - 9DLQ4CIU6V (Proline)
SB  - IM
MH  - Biopolymers/genetics/metabolism
MH  - Cerebral Cortex/metabolism/pathology
MH  - Dementia/*genetics/pathology
MH  - Female
MH  - Humans
MH  - Inclusion Bodies/metabolism/ultrastructure
MH  - Male
MH  - Neuropeptides/*genetics/metabolism
MH  - *Point Mutation
MH  - Proline
MH  - Serine
MH  - Serpins/*genetics/metabolism
EDAT- 1999/10/12 09:00
MHDA- 2001/03/23 10:01
CRDT- 1999/10/12 09:00
PHST- 1999/10/12 09:00 [pubmed]
PHST- 2001/03/23 10:01 [medline]
PHST- 1999/10/12 09:00 [entrez]
AID - 10.1038/43894 [doi]
PST - ppublish
SO  - Nature. 1999 Sep 23;401(6751):376-9. doi: 10.1038/43894.