TY - JOUR
T1 - α-internexin is present in the pathological inclusions of neuronal intermediate filament inclusion disease
AU - Cairns, Nigel J.
AU - Zhukareva, Victoria
AU - Uryu, Kunihiro
AU - Zhang, Bin
AU - Bigio, Eileen
AU - Mackenzie, Ian R A
AU - Gearing, Marla
AU - Duyckaerts, Charles
AU - Yokoo, Hideaki
AU - Nakazato, Yoichi
AU - Jaros, Evelyn
AU - Perry, Robert H.
AU - Lee, Virginia M Y
AU - Trojanowski, John Q.
N1 - Funding Information:
Support for this work was provided by grants from the National Institute on Aging of the National Institutes of Health ( AG-09215, AG-10124, AG-17586 to V.M.-Y.L. and J.Q.T., and AG-10130 and ES12068 to M.G. ), and from the Wellcome Trust ( GR066166AIA) to N.J.C. V.M.-Y.L . is the John H. Ware, 3rd Professor of Alzheimer's Research and J.Q.T. is the William Maul Measey-Truman G. Schnabel, Jr. M.D., Professor of Geriatric Medicine and Gerontology of the Center for Neurodegenerative Disease Research; University of Pennsylvania School of Medicine.
PY - 2004/6
Y1 - 2004/6
N2 - 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 α-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 α-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 α-internexin in the cytoplasmic inclusions implicates novel mechanisms of pathogenesis in NIFID and other neurological diseases with pathological accumulations of IFs.
AB - 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 α-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 α-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 α-internexin in the cytoplasmic inclusions implicates novel mechanisms of pathogenesis in NIFID and other neurological diseases with pathological accumulations of IFs.
UR - http://www.scopus.com/inward/record.url?scp=2442684337&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=2442684337&partnerID=8YFLogxK
U2 - 10.1016/S0002-9440(10)63773-X
DO - 10.1016/S0002-9440(10)63773-X
M3 - Article
C2 - 15161649
AN - SCOPUS:2442684337
VL - 164
SP - 2153
EP - 2161
JO - American Journal of Pathology
JF - American Journal of Pathology
SN - 0002-9440
IS - 6
ER -