title: FUS immunogold labeling TEM analysis of the neuronal cytoplasmic inclusions of neuronal intermediate filament inclusion disease: a frontotemporal lobar degeneration with FUS proteinopathy.
abstract: Fused in sarcoma (FUS)-immunoreactive neuronal and glial inclusions define a novel molecular pathology called FUS proteinopathy. FUS has been shown to be a component of inclusions of familial amyotrophic lateral sclerosis with FUS mutation and three frontotemporal lobar degeneration entities, including neuronal intermediate filament inclusion disease (NIFID). The pathogenic role of FUS is unknown. In addition to FUS, many neuronal cytoplasmic inclusions (NCI) of NIFID contain aggregates of α-internexin and neurofilament proteins. Herein, we have shown that: (1) FUS becomes relatively insoluble in NIFID and there are no apparent posttranslational modifications, (2) there are no pathogenic abnormalities in the FUS gene in NIFID, and (3) immunoelectron microscopy demonstrates the fine structural localization of FUS in NIFID which has not previously been described. FUS localized to euchromatin, and strongly with paraspeckles, in nuclei, consistent with its RNA/DNA-binding functions. NCI of varying morphologies were observed. Most frequent were the "loosely aggregated cytoplasmic inclusions," 81% of which had moderate or high levels of FUS immunoreactivity. Much rarer "compact cytoplasmic inclusions" and "tangled twine ball inclusions" were FUS-immunoreactive at their granular peripheries, or heavily FUS-positive throughout, respectively. Thus, FUS may aggregate in the cytoplasm and then admix with neuronal intermediate filament accumulations.
authors: Electron Microscope Division, Sussex Centre for Advanced Microscopy, John Maynard-Smith Building, School of Life Sciences, University of Sussex, Falmer, Brighton, BN1 9QG, East Sussex, UK.
authors: Tristan
authors: T
authors: Page
authors: Michael A
authors: MA
authors: Gitcho
authors: Sabrina
authors: S
authors: Mosaheb
authors: Deborah
authors: D
authors: Carter
authors: Sumi
authors: S
authors: Chakraverty
authors: Robert H
authors: RH
authors: Perry
authors: Eileen H
authors: EH
authors: Bigio
authors: Marla
authors: M
authors: Gearing
authors: Isidre
authors: I
authors: Ferrer
authors: Alison M
authors: AM
authors: Goate
authors: Nigel J
authors: NJ
authors: Cairns
authors: Julian R
authors: JR
authors: Thorpe
references: Cell. 2009 Mar 20;136(6):1001-4
references: 19303844
references: Cell. 2001 Aug 24;106(4):465-75
references: 11525732
references: Neurosci Res. 2010 Jan;66(1):131-3
references: 19833157
references: Acta Neuropathol. 2005 Oct;110(4):360-8
references: 16025283
references: Methods Mol Biol. 1999;117:99-110
references: 10327401
references: Acta Neuropathol. 2011 Feb;121(2):219-28
references: 20886222
references: J Biol Chem. 1998 Oct 23;273(43):27761-4
references: 9774382
references: Neurobiol Dis. 2004 Nov;17(2):237-49
references: 15474361
references: Nat Med. 2004 Oct;10(10):1055-63
references: 15459709
references: Curr Biol. 2002 Jan 8;12(1):13-25
references: 11790299
references: Acta Neuropathol. 2004 Sep;108(3):213-23
references: 15170578
references: Acta Neuropathol. 2009 Nov;118(5):633-45
references: 19618195
references: Ann Neurol. 2009 Apr;65(4):470-3
references: 19350673
references: Acta Neuropathol. 2005 Apr;109(4):427-32
references: 15754170
references: EMBO J. 1998 Aug 3;17(15):4442-55
references: 9687511
references: Science. 2009 Feb 27;323(5918):1208-1211
references: 19251628
references: Neuropathol Appl Neurobiol. 2003 Jun;29(3):239-53
references: 12787321
references: J Cell Biol. 2009 Sep 7;186(5):637-44
references: 19720872
references: Acta Neuropathol. 2009 Nov;118(5):617-27
references: 19830439
references: Neurobiol Aging. 2006 May;27(5):778.e1-778.e6
references: 16005115
references: Nature. 1993 Jun 17;363(6430):640-4
references: 8510758
references: J Biol Chem. 1999 Nov 26;274(48):34337-42
references: 10567410
references: J Histochem Cytochem. 1999 Dec;47(12):1633-40
references: 10567447
references: Nat Genet. 2008 May;40(5):572-4
references: 18372902
references: J Biol Chem. 2001 Sep 28;276(39):36337-43
references: 11470789
references: Ann Neurol. 2008 Apr;63(4):535-8
references: 18288693
references: Neurology. 2010 Feb 2;74(5):366-71
references: 20124201
references: Science. 2008 Mar 21;319(5870):1668-72
references: 18309045
references: Brain. 2009 Nov;132(Pt 11):2922-31
references: 19674978
references: J Cell Sci. 1997 Aug;110 ( Pt 15):1741-50
references: 9264461
references: Mol Cell Biol. 2003 Sep;23(18):6618-30
references: 12944487
references: Science. 2009 Feb 27;323(5918):1205-8
references: 19251627
references: Am J Pathol. 2004 Jun;164(6):2153-61
references: 15161649
references: J Neural Transm (Vienna). 2008 Dec;115(12):1661-71
references: 18974920
references: Clin Neuropathol. 2004 Jul-Aug;23(4):183-93
references: 15328884
references: J Biol Chem. 2009 May 1;284(18):12384-98
references: 19237541
references: BMC Cell Biol. 2008 Jul 11;9:37
references: 18620564
references: EMBO J. 2001 Apr 2;20(7):1774-84
references: 11285240
references: Brain. 2003 Oct;126(Pt 10):2291-303
references: 12876145
references: Nature. 2008 Jul 3;454(7200):126-30
references: 18509338
references: Neurosci Lett. 2003 May 8;341(3):177-80
references: 12697277
references: Neurobiol Aging. 2011 Aug;32(8):1528-9
references: 19782434
references: Acta Neuropathol. 2010 Jan;119(1):1-4
references: 19924424
references: EMBO J. 2008 Jan 23;27(2):336-49
references: 18216876
references: Neurology. 2004 Oct 26;63(8):1376-84
references: 15505152
references: Neuropathology. 2006 Oct;26(5):417-21
references: 17080718
references: Brain Pathol. 2010 May;20(3):589-97
references: 19832837
references: Lancet Neurol. 2008 May;7(5):409-16
references: 18396105
references: Mol Biol Cell. 2006 Apr;17(4):1723-33
references: 16467386
references: Oncogene. 1999 Aug 5;18(31):4515-21
references: 10442642
references: Arch Neurol. 2008 Feb;65(2):272-5
references: 18268200
references: Acta Neuropathol. 2009 Nov;118(5):605-16
references: 19669651
references: Science. 2006 Oct 6;314(5796):130-3
references: 17023659