TY  - JOUR
AU  - Neumann, Manuela
AU  - Valori, Chiara Flora
AU  - Ansorge, Olaf
AU  - Kretzschmar, Hans
AU  - Munoz, David G
AU  - Kusaka, Hirofumi
AU  - Yokota, Osamu
AU  - Ishihara, Kenji
AU  - Ang, Lee-Cyn
AU  - Bilbao, Juan M
AU  - Mackenzie, Ian R.A.
TI  - 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.
JO  - Acta neuropathologica
VL  - 124
IS  - 5
SN  - 0001-6322
CY  - Heidelberg
PB  - Springer
M1  - DZNE-2020-02978
SP  - 705-716
PY  - 2012
AB  - 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.
KW  - Adaptor Proteins, Signal Transducing: metabolism
KW  - Amyotrophic Lateral Sclerosis: genetics
KW  - Amyotrophic Lateral Sclerosis: metabolism
KW  - Brain: metabolism
KW  - Brain: pathology
KW  - DNA-Binding Proteins: metabolism
KW  - Female
KW  - Frontotemporal Lobar Degeneration: genetics
KW  - Frontotemporal Lobar Degeneration: metabolism
KW  - Gene Expression Regulation: genetics
KW  - Heterogeneous Nuclear Ribonucleoprotein A1
KW  - Heterogeneous-Nuclear Ribonucleoprotein Group A-B: metabolism
KW  - Humans
KW  - Inclusion Bodies: metabolism
KW  - Inclusion Bodies: pathology
KW  - Male
KW  - Mutation: genetics
KW  - Poly(A)-Binding Protein I: metabolism
KW  - RNA-Binding Protein EWS: metabolism
KW  - RNA-Binding Protein FUS: genetics
KW  - RNA-Binding Protein FUS: metabolism
KW  - RNA-Binding Proteins: metabolism
KW  - TATA-Binding Protein Associated Factors: metabolism
KW  - beta Karyopherins: metabolism
KW  - Adaptor Proteins, Signal Transducing (NLM Chemicals)
KW  - DNA-Binding Proteins (NLM Chemicals)
KW  - Heterogeneous Nuclear Ribonucleoprotein A1 (NLM Chemicals)
KW  - Heterogeneous-Nuclear Ribonucleoprotein Group A-B (NLM Chemicals)
KW  - KHDRBS1 protein, human (NLM Chemicals)
KW  - PABPN1 protein, human (NLM Chemicals)
KW  - Poly(A)-Binding Protein I (NLM Chemicals)
KW  - RNA-Binding Protein EWS (NLM Chemicals)
KW  - RNA-Binding Protein FUS (NLM Chemicals)
KW  - RNA-Binding Proteins (NLM Chemicals)
KW  - TAF15 protein, human (NLM Chemicals)
KW  - TATA-Binding Protein Associated Factors (NLM Chemicals)
KW  - TNPO1 protein, human (NLM Chemicals)
KW  - beta Karyopherins (NLM Chemicals)
KW  - hnRNPA1 protein, human (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:22842875
DO  - DOI:10.1007/s00401-012-1020-6
UR  - https://pub.dzne.de/record/136656
ER  -