The Intracellular Accumulation of Polymeric Neuroserpin Explains the Severity of the Dementia FENIB

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2008 Feb 13

PMID 18267959

Citations 47

Authors

Elena Miranda

Ian MacLeod

Mark J Davies

Juan Perez

Karin Romisch

Damian C Crowther

David A Lomas

Affiliations

Soon will be listed here.

Abstract

Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is an autosomal dominant dementia that is characterized by the retention of polymers of neuroserpin as inclusions within the endoplasmic reticulum (ER) of neurons. We have developed monoclonal antibodies that detect polymerized neuroserpin and have used COS-7 cells, stably transfected PC12 cell lines and transgenic Drosophila melanogaster to characterize the cellular handling of all four mutant forms of neuroserpin that cause FENIB. We show a direct correlation between the severity of the disease-causing mutation and the accumulation of neuroserpin polymers in cell and fly models of the disease. Moreover, mutant neuroserpin causes locomotor deficits in the fly allowing us to demonstrate a direct link between polymer accumulation and neuronal toxicity.

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