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@ARTICLE{Neumann:136656,
author = {Neumann, Manuela and Valori, Chiara Flora and Ansorge, Olaf
and Kretzschmar, Hans and Munoz, David G and Kusaka,
Hirofumi and Yokota, Osamu and Ishihara, Kenji and Ang,
Lee-Cyn and Bilbao, Juan M and Mackenzie, Ian R.A.},
title = {{T}ransportin 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.},
journal = {Acta neuropathologica},
volume = {124},
number = {5},
issn = {0001-6322},
address = {Heidelberg},
publisher = {Springer},
reportid = {DZNE-2020-02978},
pages = {705-716},
year = {2012},
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.},
keywords = {Adaptor Proteins, Signal Transducing: metabolism /
Amyotrophic Lateral Sclerosis: genetics / Amyotrophic
Lateral Sclerosis: metabolism / Brain: metabolism / Brain:
pathology / DNA-Binding Proteins: metabolism / Female /
Frontotemporal Lobar Degeneration: genetics / Frontotemporal
Lobar Degeneration: metabolism / Gene Expression Regulation:
genetics / Heterogeneous Nuclear Ribonucleoprotein A1 /
Heterogeneous-Nuclear Ribonucleoprotein Group A-B:
metabolism / Humans / Inclusion Bodies: metabolism /
Inclusion Bodies: pathology / Male / Mutation: genetics /
Poly(A)-Binding Protein I: metabolism / RNA-Binding Protein
EWS: metabolism / RNA-Binding Protein FUS: genetics /
RNA-Binding Protein FUS: metabolism / RNA-Binding Proteins:
metabolism / TATA-Binding Protein Associated Factors:
metabolism / beta Karyopherins: metabolism / Adaptor
Proteins, Signal Transducing (NLM Chemicals) / DNA-Binding
Proteins (NLM Chemicals) / Heterogeneous Nuclear
Ribonucleoprotein A1 (NLM Chemicals) / Heterogeneous-Nuclear
Ribonucleoprotein Group A-B (NLM Chemicals) / KHDRBS1
protein, human (NLM Chemicals) / PABPN1 protein, human (NLM
Chemicals) / Poly(A)-Binding Protein I (NLM Chemicals) /
RNA-Binding Protein EWS (NLM Chemicals) / RNA-Binding
Protein FUS (NLM Chemicals) / RNA-Binding Proteins (NLM
Chemicals) / TAF15 protein, human (NLM Chemicals) /
TATA-Binding Protein Associated Factors (NLM Chemicals) /
TNPO1 protein, human (NLM Chemicals) / beta Karyopherins
(NLM Chemicals) / hnRNPA1 protein, human (NLM Chemicals)},
cin = {AG Neumann},
ddc = {610},
cid = {I:(DE-2719)1210003},
pnm = {344 - Clinical and Health Care Research (POF3-344)},
pid = {G:(DE-HGF)POF3-344},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:22842875},
doi = {10.1007/s00401-012-1020-6},
url = {https://pub.dzne.de/record/136656},
}