Familial Encephalopathy with Neuroserpin Inclusion Bodies

Abstract

We report on a new familial neurodegenerative disease with associated dementia that has presented clinically in the fifth decade, in both genders, and in each of several generations of a large family from New York State-a pattern of inheritance consistent with an autosomal dominant mode of transmission. A key pathological finding is the presence of neuronal inclusion bodies distributed throughout the gray matter of the cerebral cortex and in certain subcortical nuclei. These inclusions are distinct from any described previously and henceforth are identified as Collins bodies. The Collins bodies can be isolated by simple biochemical procedures and have a surprisingly simple composition; neuroserpin (a serine protease inhibitor) is their predominant component. An affinity-purified antibody against neuroserpin specifically labels the Collins bodies, confirming their chemical composition. Therefore, we propose a new disease entity-familial encephalopathy with neuroserpin inclusion bodies (FENIB). The conclusion that FENIB is a previously unrecognized neurodegenerative disease is supported by finding Collins bodies in a small kindred from Oregon with familial dementia who are unrelated to the New York family. The autosomal dominant inheritance strongly suggests that FENIB is caused by mutations in the neuroserpin gene, resulting in intracellular accumulation of the mutant protein.

Mutants of Neuroserpin That Cause Dementia Accumulate as Polymers within the Endoplasmic Reticulum

“…At 12,24,48, and 72 h after transfection, cells were washed, fixed in ice-cold 4% (w/v) paraformaldehyde for 30 min at room temperature, washed again, and blocked for 60 min with phosphate-buffered saline (PBS) containing 10% (w/v) bovine serum albumin, 0.1% (v/v) Triton X-100, and 0.1% (w/v) sodium azide, and then incubated in primary antibody for 90 min. Cells were washed again, incubated with the secondary antibody for 60 min, washed, and mounted in Fluorosave (Calbiochem, through CN Biosciences, Nottingham, UK) containing 2% (w/v) 1,4-diazabicyclo-[2.2.2]octane (Sigma) and 3 g/ml 4Ј,6-diamidino-2-phenylindole (Sigma).…”

“…We have recently described an autosomal dominant dementia, familial encephalopathy with neuroserpin inclusion bodies (FENIB), 1 that is characterized by inclusions of mutant neuroserpin within cortical and subcortical neurons (11)(12)(13). This dementia is unusual in that the inclusions result from the retention of ordered polymers of neuroserpin, most likely within the endoplasmic reticulum (ER) of neurons (11).…”

“…The point at which mutant neuroserpin is retained within neurons in individuals with FENIB has been deduced from microscopic analysis of intracerebral inclusions rather than from direct studies of trafficking of the wild type or the mutant protein (12). We have therefore established a cell model that recapitulates the secretion of neuroserpin and have used it to examine the effects of the Syracuse (S49P) and Portland (S52R) mutations that cause FENIB (11,13).…”

A rat model of human FENIB (familial encephalopathy with neuroserpin inclusion bodies)

“…evidence that presence of PAS-positive intracellular inclusions in FENIB is associated with neuronal degeneration [5], apparent neuronal loss was observed in the hippocampus CA1 region of 4-12 month old Tg meg rats, when compared with nonTg littermates ( Fig. 2A-F, G).…”

“…The accumulation of neuroserpin results in formation of PAS-positive inclusions in the brain and is associated with a neurodegenerative disorder termed familial encephalopathy with neuroserpin inclusion bodies (FENIB) [5].…”