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 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.
authors.affiliation: Department of Clinical Pathology, State University of New York Health Science Center, Syracuse 13210, USA.
authors.forename: R L
authors.initials: RL
authors.lastname: Davis
authors.forename: A E
authors.initials: AE
authors.lastname: Shrimpton
authors.forename: P D
authors.initials: PD
authors.lastname: Holohan
authors.forename: C
authors.initials: C
authors.lastname: Bradshaw
authors.forename: D
authors.initials: D
authors.lastname: Feiglin
authors.forename: G H
authors.initials: GH
authors.lastname: Collins
authors.forename: P
authors.initials: P
authors.lastname: Sonderegger
authors.forename: J
authors.initials: J
authors.lastname: Kinter
authors.forename: L M
authors.initials: LM
authors.lastname: Becker
authors.forename: F
authors.initials: F
authors.lastname: Lacbawan
authors.forename: D
authors.initials: D
authors.lastname: Krasnewich
authors.forename: M
authors.initials: M
authors.lastname: Muenke
authors.forename: D A
authors.initials: DA
authors.lastname: Lawrence
authors.forename: M S
authors.initials: MS
authors.lastname: Yerby
authors.forename: C M
authors.initials: CM
authors.lastname: Shaw
authors.forename: B
authors.initials: B
authors.lastname: Gooptu
authors.forename: P R
authors.initials: PR
authors.lastname: Elliott
authors.forename: J T
authors.initials: JT
authors.lastname: Finch
authors.forename: R W
authors.initials: RW
authors.lastname: Carrell
authors.forename: D A
authors.initials: DA
authors.lastname: Lomas
mesh_terms: D001704:Biopolymers / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003704:Dementia / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D009479:Neuropeptides / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D011392:Proline; D012694:Serine; D015843:Serpins / Q000235:genetics* / Q000378:metabolism; D000097522:Neuroserpin
chemical_list: D001704:Biopolymers; D009479:Neuropeptides; D011392:Proline; D012694:Serine; D015843:Serpins; D000097522:Neuroserpin