Human Molecular Genetics Advance Access originally published online on February 11, 2008
Human Molecular Genetics 2008 17(11):1527-1539; doi:10.1093/hmg/ddn041
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The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB
1 Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK 2 Departamento de Biología Celular, Genética y Fisiología, Universidad de Málaga, Facultad de Ciencias, Campus de Teatinos, Málaga 29071, España 3 Center for Integrative Biology, University of Trento, via delle Regole, 101, 38100 Mattarello (Trento), Italy 4 Department of Genetics, University of Cambridge, Downing Street, Cambridge CB2 3EH, UK
* To whom correspondence should be addressed. Tel: +44 1223336825; Fax: +44 1223336827; Email: em285{at}cam.ac.uk
Received December 17, 2007; Accepted February 7, 2008
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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