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1.
Figure 5

Figure 5. From: Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis.

Multiple neuropathologic markers co-accumulate in FUSΔ14mice NCIs. Double labelling for FUS (anti-V5; A, E and I) and P62 (B), PABP1 (F) and α-internexin (J). Colocalization shown in merged image (D, H and L). Nuclei were counterstained with DAPI (C, G, and K). Scale bar: 20 μm.

Christophe Verbeeck, et al. Mol Neurodegener. 2012;7:53-53.
2.
Figure 4

Figure 4. From: Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis.

Ubiquitin co-localizes to FUS-positive inclusions in hFUSΔ14mice. Confocal image showing FUS located in nucleus in FUSWT mice (A), increased cytoplasmic distribution of FUS in FUSR521C mice (B), and accumulation of FUS into NCIs in FUSΔ14 mice (C) that co-labels with ubiquitin (F and L). Nuclei were counterstained with DAPI (G, H and I). FUS detected with anti-V5 (A, B, C). Scale bar: 10 μm.

Christophe Verbeeck, et al. Mol Neurodegener. 2012;7:53-53.
3.
Figure 6

Figure 6. From: Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis.

Endogenous TDP-43 is not redistributed in FUSWT,FUSR521Cand FUSΔ14mouse brain. Mouse TDP-43 is predominantly in the nucleus (DAB immunohistochemistry; A, B, and C). Double-label immunofluorescence of TDP-43 and FUSwt, FUSR521C or FUSΔ14 mice (anti-V5; D-O). FUS is distributed to the nucleus in FUSWT mice (D), increased in the neuronal cytoplasm in FUSR521C mice (H), and accumulates as inclusions in the neuronal cytoplasm in FUSΔ14 mice (L). TDP-43 staining is nuclear in FUSWT, FUSR521C and FUSΔ14 mice (E, I and M). Nuclei were counterstained with DAPI. Scale bar: 20 μm.

Christophe Verbeeck, et al. Mol Neurodegener. 2012;7:53-53.
4.
Figure 2

Figure 2. From: Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis.

FUS mutations cause an aberrant subcellular redistribution in mouse neurons. A representative immunoblot (A) of the V5 tagged FUS proteins extracted from AAV injected mouse brains. Tissue extracts from FUSWT, FUSR521C, and FUSΔ14 brain were separated into soluble fractions from the cytoplasm and nucleus. Histone 3 staining was used as a nuclear marker to verify extraction fidelity. (B) The ratio of cytoplasmic FUS to nuclear FUS was calculated based on quantification of immunoblots for different FUS constructs (n=4; S.E.M.). A higher ratio of FUSR521C and FUSΔ14 are found in the cytoplasm. ** P<0.01 and ***P<0.001. (C) FUSR521C and FUSΔ14 protein are more insoluble than FUSWT.

Christophe Verbeeck, et al. Mol Neurodegener. 2012;7:53-53.
5.
Figure 3

Figure 3. From: Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis.

Neuropathology of SBT FUSΔ14mice is similar to human FUS proteinopathies (A-P). Adjacent sections from the cerebral cortex of eGFP (A-D), FUSWT (E-H), FUSR521C (I-L), and FUSΔ14 (M-P) mice stained with protein NCI markers found in aFTLD-U, NIFID, BIBD and hematoxylin-eosin (H&E). (M) Only FUSΔ14 brains contain ubiquitinated NCIs. (N) Hematoxylin-eosin (H&E) staining of FUSΔ14 cerebral cortex shows cytoplasmic basophilic inclusions (arrows). (O) NCIs are infrequently positive for α-internexin, similar to the pathological NCIs found in NIFID cases. (P) Some NCI in the cerebral cortex of FUSΔ14 mice contain the stress granule marker protein PABP-1. Scale bar: 100 μm. Slides are orientated to a common blood vessel (arrow head) to serve as a landmark (M-P).

Christophe Verbeeck, et al. Mol Neurodegener. 2012;7:53-53.
6.
Figure 1

Figure 1. From: Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis.

Generation of Human Fused in Sarcoma (FUS) mouse models using rAAV1 and SBT. (A). Diagram of FUSWT, FUSR521C, and FUSΔ14 expression constructs. All FUS constructs were cloned with a V5 epitope tag on the amino-terminus to aid immunodetection. The major protein domains of FUS are highlighted. QGSY=Gln-Gly-Ser-Tyr rich region. Glycine rich region. NES=nuclear export signal. RRM= RNA recognition motif. RGG= Arg-Gly-Gly-rich motif. ZNF=zinc finger motif. PY-NLS=Pro-Tyr nuclear localisation signal. (B) to (G). Immunohistochemistry (anti-V5 antibody) detects widespread expression of FUSWT, FUSR521C, and FUSΔ14 in cerebral cortex and dentate gyrus (DG). Wild type FUS is mainly localized in the nuclei (B insert). Intense nuclear V5 staining in cerebral cortex (B) and weak cytoplasmic v5 staining in DG (E). In the FUSR521C model, FUS is no longer predominantly located in the nucleus, but also found in the soma and dendrites (C and F). FUSΔ14 mice have a dramatic translocation of FUS from the nucleus to the cytoplasm, and formation of neuronal cytoplasmic inclusions (NCIs) (D and G). Scale bar: 100 μm (H). Histogram showing the percent of nuclear and cytoplasmic v5 staining,cytoplasmic inclusion in cerebral cortex. (n=4; S.E.M.) * P<0.05, **P<0.01 and ***P<0.001, one way ANOVA.

Christophe Verbeeck, et al. Mol Neurodegener. 2012;7:53-53.

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