title: alpha-internexin is present in the pathological inclusions of neuronal intermediate filament inclusion disease.
abstract: Neuronal intermediate filament (IF) inclusion disease (NIFID) is a novel neurological disease of early onset with a variable clinical phenotype including frontotemporal dementia, pyramidal, and extrapyramidal signs. Pathologically, in affected areas, there is neuronal loss, astrocytosis, and neuronal intracytoplasmic aggregates of abnormal neuronal IFs that contain neither tau nor alpha-synuclein. Thus, to characterize the neuronal IF protein profile of inclusions in NIFID, immunohistochemistry (IHC) was performed on 10 cases of NIFID, four normal aged controls (NL), and two cases of Alzheimer's disease (AD) using a panel of anti-neuronal IF proteins. Immunoelectron microscopy was performed on selected cases and frozen tissue from the frontal lobe of four cases was used for biochemical studies including sequential extractions and Western blotting. Based on these studies, we report here for the first time that alpha-internexin, a neuronal IF protein, is present within the inclusions of NIFID as are all three neurofilament subunits: heavy, medium, and light. Thus, all class IV neuronal IF proteins are present within the pathological inclusions of this disease. Biochemistry revealed that IF aggregates were soluble in sodium dodecyl sulfate (SDS) and no post-translational modification was detected when compared with Alzheimer's disease or aged control brains. Hence, we conclude that NIFID is characterized by the pathological cytoplasmic aggregation of all class IV neuronal IF proteins in brain. The discovery of alpha-internexin in the cytoplasmic inclusions implicates novel mechanisms of pathogenesis in NIFID and other neurological diseases with pathological accumulations of IFs.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283, USA. cairns@mail.med.upenn.edu
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Cairns
authors.forename: Victoria
authors.initials: V
authors.lastname: Zhukareva
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Uryu
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Eileen
authors.initials: E
authors.lastname: Bigio
authors.forename: Ian R A
authors.initials: IR
authors.lastname: Mackenzie
authors.forename: Marla
authors.initials: M
authors.lastname: Gearing
authors.forename: Charles
authors.initials: C
authors.lastname: Duyckaerts
authors.forename: Hideaki
authors.initials: H
authors.lastname: Yokoo
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Nakazato
authors.forename: Evelyn
authors.initials: E
authors.lastname: Jaros
authors.forename: Robert H
authors.initials: RH
authors.lastname: Perry
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
mesh_terms: D000328:Adult; D017668:Age of Onset; D000544:Alzheimer Disease / Q000473:pathology; D001921:Brain / Q000033:anatomy & histology / Q000473:pathology / Q000648:ultrastructure; D002352:Carrier Proteins / Q000032:analysis*; D003586:Cytomegalovirus Infections / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007381:Intermediate Filament Proteins / Q000032:analysis; D007382:Intermediate Filaments / Q000473:pathology* / Q000648:ultrastructure; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000032:analysis; D009929:Organ Size; D016019:Survival Analysis
chemical_list: D002352:Carrier Proteins; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C046643:alpha-internexin