Top

Published in:

01-09-2012 | Original Paper

Localization of fused in sarcoma (FUS) protein to the post-synaptic density in the brain

Authors: Naoya Aoki, Shinji Higashi, Ito Kawakami, Zen Kobayashi, Masato Hosokawa, Omi Katsuse, Takashi Togo, Yoshio Hirayasu, Haruhiko Akiyama

Published in: Acta Neuropathologica | Issue 3/2012

Abstract

Mutations in the fused in sarcoma (FUS) gene are linked to a form of familial amyotrophic lateral sclerosis (ALS), ALS6. The FUS protein is a major component of the ubiquitin-positive neuronal cytoplasmic inclusions in both ALS6 and some rare forms of frontotemporal lobar degeneration (FTLD). The latter are now collectively referred to as FTLD-FUS. In the present study, we investigated the localization of FUS in human and mouse brains. FUS was detected by western blot as an approximately 72 kDa protein in both human and mouse brains. Immunohistochemistry using lightly fixed tissue sections of human and mouse brains revealed FUS-positive granular staining in the neuropil, in addition to nuclear staining. Such granules are abundant in the gray matter of the brainstem and spinal cord. They are not frequent in the telencephalon. At the light microscopic level, FUS-positive granules are often co-localized with synaptophysin and present in association with microtubule-associated protein 2-positive dendrites. In the synaptosomal fraction of mouse brain, FUS is detected mainly in the post-synaptic density fraction. Thus, while FUS is primarily a nuclear protein, it may also play a role in dendrites. In the brains of patients with FTLD with TDP-43 deposition (FTLD-TDP), the number of FUS-positive granules in the cortex is increased compared with control cases. The increase in Alzheimer’s disease (AD) is less remarkable but still significant. The dendritic localization of FUS and its increase in FTLD-TDP and AD may have some implication for the pathophysiology of neurodegenerative diseases.

Available only for authorised users

(1997) Consensus recommendations for the postmortem diagnosis of Alzheimer’s disease. The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer’s Disease. Neurobiol Aging 18:S1–S2

Andersson MK, Stahlberg A, Arvidsson Y, Olofsson A, Semb H, Stenman G, Nilsson O, Aman P (2008) The multifunctional FUS, EWS and TAF15 proto-oncoproteins show cell type-specific expression patterns and involvement in cell spreading and stress response. BMC Cell Biol 9:37PubMedCrossRef

Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H, Mann D, Tsuchiya K, Yoshida M, Hashizume Y, Oda T (2006) TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun 351:602–611PubMedCrossRef

Arai T, Mackenzie IR, Hasegawa M, Nonoka T, Niizato K, Tsuchiya K, Iritani S, Onaya M, Akiyama H (2009) Phosphorylated TDP-43 in Alzheimer’s disease and dementia with Lewy bodies. Acta Neuropathol 117:125–136PubMedCrossRef

Armstrong RA, Gearing M, Bigio EH, Cruz-Sanchez FF, Duyckaerts C, Mackenzie IR, Perry RH, Skullerud K, Yokoo H, Cairns NJ (2011) The spectrum and severity of FUS-immunoreactive inclusions in the frontal and temporal lobes of ten cases of neuronal intermediate filament inclusion disease. Acta Neuropathol 121:219–228PubMedCrossRef

Belly A, Moreau-Gachelin F, Sadoul R, Goldberg Y (2005) Delocalization of the multifunctional RNA splicing factor TLS/FUS in hippocampal neurones: exclusion from the nucleus and accumulation in dendritic granules and spine heads. Neurosci Lett 379:152–157PubMedCrossRef

Bian H, Grossman M (2007) Frontotemporal lobar degeneration: recent progress in antemortem diagnosis. Acta Neuropathol 114:23–29PubMedCrossRef

Bosco DA, Lemay N, Ko HK, Zhou H, Burke C, Kwiatkowski TJ Jr, Sapp P, McKenna-Yasek D, Brown RH Jr, Hayward LJ (2010) Mutant FUS proteins that cause amyotrophic lateral sclerosis incorporate into stress granules. Hum Mol Genet 19:4160–4175PubMedCrossRef

Bouvier D, Corera AT, Tremblay ME, Riad M, Chagnon M, Murai KK, Pasquale EB, Fon EA, Doucet G (2008) Pre-synaptic and post-synaptic localization of EphA4 and EphB2 in adult mouse forebrain. J Neurochem 106:682–695PubMedCrossRef

10.

Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, White CL 3rd, Schneider JA, Grinberg LT, Halliday G, Duyckaerts C, Lowe JS, Holm IE, Tolnay M, Okamoto K, Yokoo H, Murayama S, Woulfe J, Munoz DG, Dickson DW, Ince PG, Trojanowski JQ, Mann DM (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol 114:5–22PubMedCrossRef

11.

Dormann D, Rodde R, Edbauer D, Bentmann E, Fischer I, Hruscha A, Than ME, Mackenzie IR, Capell A, Schmid B, Neumann M, Haass C (2010) ALS-associated fused in sarcoma (FUS) mutations disrupt transportin-mediated nuclear import. EMBO J 29:2841–2857PubMedCrossRef

12.

Fujii R, Okabe S, Urushido T, Inoue K, Yoshimura A, Tachibana T, Nishikawa T, Hicks GG, Takumi T (2005) The RNA binding protein TLS is translocated to dendritic spines by mGluR5 activation and regulates spine morphology. Curr Biol 15:587–593PubMedCrossRef

13.

Fujii R, Takumi T (2005) TLS facilitates transport of mRNA encoding an actin-stabilizing protein to dendritic spines. J Cell Sci 118:5755–5765PubMedCrossRef

14.

Geser F, Brandmeir NJ, Kwong LK, Martinez-Lage M, Elman L, McCluskey L, Xie SX, Lee VM, Trojanowski JQ (2008) Evidence of multisystem disorder in whole-brain map of pathological TDP-43 in amyotrophic lateral sclerosis. Arch Neurol 65:636–641PubMedCrossRef

15.

Gitcho MA, Baloh RH, Chakraverty S, Mayo K, Norton JB, Levitch D, Hatanpaa KJ, White CL 3rd, Bigio EH, Caselli R, Baker M, Al-Lozi MT, Morris JC, Pestronk A, Rademakers R, Goate AM, Cairns NJ (2008) TDP-43 A315T mutation in familial motor neuron disease. Ann Neurol 63:535–538PubMedCrossRef

16.

Hahn CG, Banerjee A, Macdonald ML, Cho DS, Kamins J, Nie Z, Borgmann-Winter KE, Grosser T, Pizarro A, Ciccimaro E, Arnold SE, Wang HY, Blair IA (2009) The post-synaptic density of human postmortem brain tissues: an experimental study paradigm for neuropsychiatric illnesses. PLoS ONE 4:e5251PubMedCrossRef

17.

Higashi S, Iseki E, Minegishi M, Togo T, Kabuta T, Wada K (2010) GIGYF2 is present in endosomal compartments in the mammalian brains and enhances IGF-1-induced ERK1/2 activation. J Neurochem 115:423–437PubMedCrossRef

18.

Higashi S, Moore DJ, Minegishi M, Kasanuki K, Fujishiro H, Kabuta T, Togo T, Katsuse O, Uchikado H, Furukawa Y, Hino H, Kosaka K, Sato K, Arai H, Wada K, Iseki E (2011) Localization of MAP1-LC3 in vulnerable neurons and Lewy bodies in brains of patients with dementia with Lewy bodies. J Neuropathol Exp Neurol 70:264–280PubMedCrossRef

19.

Iida J, Nishimura W, Yao I, Hata Y (2002) Synaptic localization of membrane-associated guanylate kinase-interacting protein mediated by the pleckstrin homology domain. Eur J Neurosci 15:1493–1498PubMedCrossRef

20.

Kabashi E, Valdmanis PN, Dion P, Spiegelman D, McConkey BJ, Vande Velde C, Bouchard JP, Lacomblez L, Pochigaeva K, Salachas F, Pradat PF, Camu W, Meininger V, Dupre N, Rouleau GA (2008) TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat Genet 40:572–574PubMedCrossRef

21.

Kwiatkowski TJ Jr, Bosco DA, Leclerc AL, Tamrazian E, Vanderburg CR, Russ C, Davis A, Gilchrist J, Kasarskis EJ, Munsat T, Valdmanis P, Rouleau GA, Hosler BA, Cortelli P, de Jong PJ, Yoshinaga Y, Haines JL, Pericak-Vance MA, Yan J, Ticozzi N, Siddique T, McKenna-Yasek D, Sapp PC, Horvitz HR, Landers JE, Brown RH Jr (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208PubMedCrossRef

22.

Lanson NA Jr, Maltare A, King H, Smith R, Kim JH, Taylor JP, Lloyd TE, Pandey UB (2011) A Drosophila model of FUS-related neurodegeneration reveals genetic interaction between FUS and TDP-43. Hum Mol Genet 20:2510–2523PubMedCrossRef

23.

Lashley T, Rohrer JD, Bandopadhyay R, Fry C, Ahmed Z, Isaacs AM, Brelstaff JH, Borroni B, Warren JD, Troakes C, King A, Al-Saraj S, Newcombe J, Quinn N, Ostergaard K, Schroder HD, Bojsen-Moller M, Braendgaard H, Fox NC, Rossor MN, Lees AJ, Holton JL, Revesz T (2011) A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies. Brain 134:2548–2564PubMedCrossRef

24.

Liu-Yesucevitz L, Bassell GJ, Gitler AD, Hart AC, Klann E, Richter JD, Warren ST, Wolozin B (2011) Local RNA translation at the synapse and in disease. J Neurosci 31:16086–16093PubMedCrossRef

25.

Mackenzie IR, Ansorge O, Strong M, Bilbao J, Zinman L, Ang LC, Baker M, Stewart H, Eisen A, Rademakers R, Neumann M (2011) Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation. Acta Neuropathol 122:87–98PubMedCrossRef

26.

Mackenzie IR, Munoz DG, Kusaka H, Yokota O, Ishihara K, Roeber S, Kretzschmar HA, Cairns NJ, Neumann M (2011) Distinct pathological subtypes of FTLD-FUS. Acta Neuropathol 121:207–218PubMedCrossRef

27.

Mackenzie IR, Neumann M, Baborie A, Sampathu DM, Du Plessis D, Jaros E, Perry RH, Trojanowski JQ, Mann DM, Lee VM (2011) A harmonized classification system for FTLD-TDP pathology. Acta Neuropathol 122:111–113PubMedCrossRef

28.

Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, Kovacs GG, Ghetti B, Halliday G, Holm IE, Ince PG, Kamphorst W, Revesz T, Rozemuller AJ, Kumar-Singh S, Akiyama H, Baborie A, Spina S, Dickson DW, Trojanowski JQ, Mann DM (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol 117:15–18PubMedCrossRef

29.

Mackenzie IR, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, Kovacs GG, Ghetti B, Halliday G, Holm IE, Ince PG, Kamphorst W, Revesz T, Rozemuller AJ, Kumar-Singh S, Akiyama H, Baborie A, Spina S, Dickson DW, Trojanowski JQ, Mann DM (2010) Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: an update. Acta Neuropathol 119:1–4PubMedCrossRef

30.

Munoz DG, Neumann M, Kusaka H, Yokota O, Ishihara K, Terada S, Kuroda S, Mackenzie IR (2009) FUS pathology in basophilic inclusion body disease. Acta Neuropathol 118:617–627PubMedCrossRef

31.

Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554PubMedCrossRef

32.

Neumann M, Rademakers R, Roeber S, Baker M, Kretzschmar HA, Mackenzie IR (2009) A new subtype of frontotemporal lobar degeneration with FUS pathology. Brain 132:2922–2931PubMedCrossRef

33.

Neumann M, Roeber S, Kretzschmar HA, Rademakers R, Baker M, Mackenzie IR (2009) Abundant FUS-immunoreactive pathology in neuronal intermediate filament inclusion disease. Acta Neuropathol 118:605–616PubMedCrossRef

34.

Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM (2006) Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314:130–133PubMedCrossRef

35.

Prasad DD, Ouchida M, Lee L, Rao VN, Reddy ES (1994) TLS/FUS fusion domain of TLS/FUS-erg chimeric protein resulting from the t(16;21) chromosomal translocation in human myeloid leukemia functions as a transcriptional activation domain. Oncogene 9:3717–3729PubMed

36.

Ringholz GM, Appel SH, Bradshaw M, Cooke NA, Mosnik DM, Schulz PE (2005) Prevalence and patterns of cognitive impairment in sporadic ALS. Neurology 65:586–590PubMedCrossRef

37.

Rosso SM, Donker Kaat L, Baks T, Joosse M, de Koning I, Pijnenburg Y, de Jong D, Dooijes D, Kamphorst W, Ravid R, Niermeijer MF, Verheij F, Kremer HP, Scheltens P, van Duijn CM, Heutink P, van Swieten JC (2003) Frontotemporal dementia in The Netherlands: patient characteristics and prevalence estimates from a population-based study. Brain 126:2016–2022PubMedCrossRef

38.

Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE (2008) TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319:1668–1672PubMedCrossRef

39.

The Lund and Manchester Groups (1994) Clinical and neuropathological criteria for frontotemporal dementia. J Neurol Neurosurg Psychiatry 57:416–418CrossRef

40.

Van Deerlin VM, Leverenz JB, Bekris LM, Bird TD, Yuan W, Elman LB, Clay D, Wood EM, Chen-Plotkin AS, Martinez-Lage M, Steinbart E, McCluskey L, Grossman M, Neumann M, Wu IL, Yang WS, Kalb R, Galasko DR, Montine TJ, Trojanowski JQ, Lee VM, Schellenberg GD, Yu CE (2008) TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol 7:409–416PubMedCrossRef

41.

Vance C, Rogelj B, Hortobagyi T, De Vos KJ, Nishimura AL, Sreedharan J, Hu X, Smith B, Ruddy D, Wright P, Ganesalingam J, Williams KL, Tripathi V, Al-Saraj S, Al-Chalabi A, Leigh PN, Blair IP, Nicholson G, de Belleroche J, Gallo JM, Miller CC, Shaw CE (2009) Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323:1208–1211PubMedCrossRef

42.

Wang HY, Wang IF, Bose J, Shen CK (2004) Structural diversity and functional implications of the eukaryotic TDP gene family. Genomics 83:130–139PubMedCrossRef

43.

Yokoseki A, Shiga A, Tan CF, Tagawa A, Kaneko H, Koyama A, Eguchi H, Tsujino A, Ikeuchi T, Kakita A, Okamoto K, Nishizawa M, Takahashi H, Onodera O (2008) TDP-43 mutation in familial amyotrophic lateral sclerosis. Ann Neurol 63:538–542PubMedCrossRef

44.

Zinszner H, Sok J, Immanuel D, Yin Y, Ron D (1997) TLS (FUS) binds RNA in vivo and engages in nucleo-cytoplasmic shuttling. J Cell Sci 110:1741–1750PubMed

Title: Localization of fused in sarcoma (FUS) protein to the post-synaptic density in the brain
Authors: Naoya Aoki
Shinji Higashi
Ito Kawakami
Zen Kobayashi
Masato Hosokawa
Omi Katsuse
Takashi Togo
Yoshio Hirayasu
Haruhiko Akiyama
Publication date: 01-09-2012
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 3/2012
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-012-0984-6

At a glance: The STEP trials

Springer Medicine

Localization of fused in sarcoma (FUS) protein to the post-synaptic density in the brain

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2012

Low rate of R132H IDH1 mutation in infratentorial and spinal cord grade II and III diffuse gliomas

Reduced astrocytic NF-κB activation by laquinimod protects from cuprizone-induced demyelination

Targeting intracerebral inflammation in multiple sclerosis: is it feasible?

Fingolimod attenuates ceramide-induced blood–brain barrier dysfunction in multiple sclerosis by targeting reactive astrocytes

K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas

The genetics and neuropathology of neurodegenerative disorders: perspectives and implications for research and clinical practice