title: The intracellular accumulation of polymeric neuroserpin explains the severity of the dementia FENIB.
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.
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK. em285@cam.ac.uk
authors.forename: Elena
authors.initials: E
authors.lastname: Miranda
authors.forename: Ian
authors.initials: I
authors.lastname: MacLeod
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Davies
authors.forename: Juan
authors.initials: J
authors.lastname: Pérez
authors.forename: Karin
authors.initials: K
authors.lastname: Römisch
authors.forename: Damian C
authors.initials: DC
authors.lastname: Crowther
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000911:Antibodies, Monoclonal / Q000276:immunology; D019556:COS Cells; D002522:Chlorocebus aethiops; D003704:Dementia / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000032:analysis* / Q000235:genetics / Q000378:metabolism*; D016716:PC12 Cells; D011108:Polymers / Q000032:analysis / Q000378:metabolism; D051381:Rats; D015843:Serpins / Q000032:analysis* / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000097522:Neuroserpin
chemical_list: D000911:Antibodies, Monoclonal; D009479:Neuropeptides; D011108:Polymers; D015843:Serpins; D000097522:Neuroserpin