title: Transportin 1 accumulates specifically with FET proteins but no other transportin cargos in FTLD-FUS and is absent in FUS inclusions in ALS with FUS mutations.
abstract: Accumulation of the DNA/RNA binding protein fused in sarcoma (FUS) as inclusions in neurons and glia is the pathological hallmark of amyotrophic lateral sclerosis patients with mutations in FUS (ALS-FUS) as well as in several subtypes of frontotemporal lobar degeneration (FTLD-FUS), which are not associated with FUS mutations. Despite some overlap in the phenotype and neuropathology of FTLD-FUS and ALS-FUS, significant differences of potential pathomechanistic relevance were recently identified in the protein composition of inclusions in these conditions. While ALS-FUS showed only accumulation of FUS, inclusions in FTLD-FUS revealed co-accumulation of all members of the FET protein family, that include FUS, Ewing's sarcoma (EWS) and TATA-binding protein-associated factor 15 (TAF15) suggesting a more complex disturbance of transportin-mediated nuclear import of proteins in FTLD-FUS compared to ALS-FUS. To gain more insight into the mechanisms of inclusion body formation, we investigated the role of Transportin 1 (Trn1) as well as 13 additional cargo proteins of Transportin in the spectrum of FUS-opathies by immunohistochemistry and biochemically. FUS-positive inclusions in six ALS-FUS cases including four different mutations did not label for Trn1. In sharp contrast, the FET-positive pathology in all FTLD-FUS subtypes was also strongly labeled for Trn1 and often associated with a reduction in the normal nuclear staining of Trn1 in inclusion bearing cells, while no biochemical changes of Trn1 were detectable in FTLD-FUS. Notably, despite the dramatic changes in the subcellular distribution of Trn1 in FTLD-FUS, alterations of its cargo proteins were restricted to FET proteins and no changes in the normal physiological staining of 13 additional Trn1 targets, such as hnRNPA1, PAPBN1 and Sam68, were observed in FTLD-FUS. These data imply a specific dysfunction in the interaction between Trn1 and FET proteins in the inclusion body formation in FTLD-FUS. Moreover, the absence of Trn1 in ALS-FUS provides further evidence that ALS-FUS and FTLD-FUS have different underlying pathomechanisms.
authors: Institute of Neuropathology, University Hospital Zurich, Switzerland. Manuela.Neumann@med.uni-tuebingen.de
authors: Manuela
authors: M
authors: Neumann
authors: Chiara F
authors: CF
authors: Valori
authors: Olaf
authors: O
authors: Ansorge
authors: Hans A
authors: HA
authors: Kretzschmar
authors: David G
authors: DG
authors: Munoz
authors: Hirofumi
authors: H
authors: Kusaka
authors: Osamu
authors: O
authors: Yokota
authors: Kenji
authors: K
authors: Ishihara
authors: Lee-Cyn
authors: LC
authors: Ang
authors: Juan M
authors: JM
authors: Bilbao
authors: Ian R A
authors: IR
authors: Mackenzie
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000235:genetics; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B / Q000378:metabolism; D006801:Humans; D002479:Inclusion Bodies / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation / Q000235:genetics; D039122:Poly(A)-Binding Protein I / Q000378:metabolism; D034802:RNA-Binding Protein EWS / Q000378:metabolism; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism; D035381:TATA-Binding Protein Associated Factors / Q000378:metabolism*; D028961:beta Karyopherins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D000076245:Heterogeneous Nuclear Ribonucleoprotein A1; D034481:Heterogeneous-Nuclear Ribonucleoprotein Group A-B; C489559:KHDRBS1 protein, human; C576588:PABPN1 protein, human; D039122:Poly(A)-Binding Protein I; D034802:RNA-Binding Protein EWS; D034702:RNA-Binding Protein FUS; D016601:RNA-Binding Proteins; C102041:TAF15 protein, human; D035381:TATA-Binding Protein Associated Factors; C108121:TNPO1 protein, human; D028961:beta Karyopherins; C000619656:hnRNPA1 protein, human