Low Level of Expression of C-Terminally Truncated Human FUS Causes Extensive Changes in the Spinal Cord Transcriptome of Asymptomatic Transgenic Mice

Lysikova, Ekaterina A.; Funikov, Sergei; Rezvykh, Alexander P.; Chaprov, Kirill; Kukharsky, Michail S.; Ustyugov, Aleksey A; Deykin, Alexey V.; Flyamer, Ilya M.; Boyle, Shelagh; Бачурин, С. О.; Ninkina, Natalia; Buchman, Vladimir L.

doi:10.1007/s11064-020-02999-z

Cited by 4 publications

(2 citation statements)

References 54 publications

(75 reference statements)

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“…The low level of expression in the spinal cord was not sufficient to trigger the development of motor phenotype in L-FUS mice, although RNA sequencing identified a set of genes that change their expression in the spinal cord of these mice. 10 Here we show that L-FUS mice develop behavioural impairments. At the age of 5 months these animals display increased impulsivity, decreased anxiety and compromised social interaction behaviour.…”

Section: Expression Of Als/ftld-associated Genes In Transgenic Rodentsmentioning

confidence: 62%

“…Separation of proteins in sodium dodecyl sulphatepolyacrylamide gel electrophoresis and consequent semidry transfer on polyvinylidene difluoride membrane (GE Healthcare) were performed as described elsewhere. 10,11 Human FUS protein was detected using rabbit polyclonal antibody 14080 (a kind gift from Don Cleveland) specific to the N-terminal epitope of human FUS protein, secondary anti-rabbit horseradish peroxidase-conjugated antibodies (GE Healthcare) and…”

Section: Protein Extraction and Western Blot Analysismentioning

confidence: 99%

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Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration

Lysikova

Kukharsky

Chaprov

et al. 2019

Genes Brain and Behavior

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Multiple clinical and experimental evidences suggest that amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are members of a disease continuum. Pathological inclusions of fused in sarcoma (FUS) protein have been observed in subsets of patients with these diseases but their anatomical distribution is different for two diseases. These structures are present in motor neurons in ALS cases but in cortical neurons in FTLD cases. Expression of a C‐terminally truncated form of human FUS causes an early onset and progressive motor neuron pathology in transgenic mice but only when these neurons express a certain level of this protein. Severe motor dysfunction and early lethality of mice with expression above this level prevent their use for studies of FTLD‐related pathology caused by expression of this form of FUS. In the present study, we used another line of mice expressing the same protein but not developing any signs of motor system dysfunction due to substantially lower level of transgene expression in motor neurons. In a set of tests 5‐month old mice displayed certain behavioural abnormalities, including increased impulsivity, decreased anxiety and compromised social interaction, which recapitulate behaviour characteristics typically seen in FTLD patients.

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Section: Expression Of Als/ftld-associated Genes In Transgenic Rodentsmentioning

confidence: 62%

Section: Protein Extraction and Western Blot Analysismentioning

confidence: 99%

Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration

Lysikova

Kukharsky

Chaprov

et al. 2019

Genes Brain and Behavior

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Abl kinase-mediated FUS Tyr526 phosphorylation alters nucleocytoplasmic FUS localization in FTLD-FUS

Motaln

Čerček

Yamoah

et al. 2023

Brain

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Nuclear to cytoplasmic mislocalization and aggregation of multiple RNA-binding proteins (RBPs), including Fused in sarcoma (FUS), are the main neuropathological features of the majority of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal lobular degeneration (FTLD). In ALS-FUS these aggregates arise from disease-associated mutations in FUS, whereas in FTLD-FUS the cytoplasmic inclusions do not contain mutant FUS, suggesting different molecular mechanisms of FUS pathogenesis in FTLD that remain to be investigated. We have previously shown that phosphorylation of the C-terminal Tyr526 of FUS results in increased cytoplasmic retention of FUS due to impaired binding to the nuclear import receptor Transportin 1 (TNPO1). Inspired by the above notions, in the current study we developed a novel antibody against the C-terminally phosphorylated Tyr526 FUS (FUSp-Y526) that is specifically capable of recognizing phosphorylated cytoplasmic FUS, which is poorly recognized by other commercially available FUS antibodies. Using this FUSp-Y526 antibody, we demonstrated a FUS phosphorylation-specific effect on the cytoplasmic distribution of soluble and insoluble FUSp-Y526 in various cells and confirmed the involvement of the Src kinase family in Tyr526 FUS phosphorylation. In addition, we found that FUSp-Y526 expression pattern corelates with active pSrc/pAbl kinases in specific brain regions of mice, indicating preferential involvement of cAbl in the cytoplasmic mislocalization of FUSp-Y526 in cortical neurons. Finally, the pattern of immunoreactivity of active cAbl kinase and FUSp-Y526 revealed altered cytoplasmic distribution of FUSp-Y526 in cortical neurons of post-mortem frontal cortex tissue from FTLD patients compared with controls. The overlap of FUSp-Y526 and FUS signals was found preferentially in small diffuse inclusions and was absent in mature aggregates, suggesting possible involvement of FUSp-Y526 in the formation of early toxic FUS aggregates in the cytoplasm that are largely undetected by commercially available FUS antibodies. Given the overlapping patterns of cAbl activity and FUSp-Y526 distribution in cortical neurons, and cAbl induced sequestration of FUSp-Y526 into G3BP1 positive granules in stressed cells, we propose that cAbl kinase is actively involved in mediating cytoplasmic mislocalization and promoting toxic aggregation of wild-type FUS in the brains of FTLD patients, as a novel putative underlying mechanism of FTLD-FUS pathophysiology and progression.

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A bioisostere of Dimebon/Latrepirdine delays the onset and slows the progression of pathology in FUS transgenic mice

et al. 2021

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Aims To assess effects of DF402, a bioisostere of Dimebon/Latrepirdine, on the disease progression in the transgenic model of amyotrophic lateral sclerosis (ALS) caused by expression of pathogenic truncated form of human FUS protein. Methods Mice received DF402 from the age of 42 days and the onset of clinical signs, the disease duration and animal lifespan were monitored for experimental and control animals, and multiple parameters of their gait were assessed throughout the pre‐symptomatic stage using CatWalk system followed by a bioinformatic analysis. RNA‐seq was used to compare the spinal cord transcriptomes of wild‐type, untreated, and DF402‐treated FUS transgenic mice. Results DF402 delays the onset and slows the progression of pathology. We developed a CatWalk analysis protocol that allows detection of gait changes in FUS transgenic mice and the effect of DF402 on their gait already at early pre‐symptomatic stage. At this stage, a limited number of genes significantly change expression in transgenic mice and for 60% of these genes, DF402 treatment causes the reversion of the expression pattern. Conclusion DF402 slows down the disease progression in the mouse model of ALS, which is consistent with previously reported neuroprotective properties of Dimebon and its other bioisosteres. These results suggest that these structures can be considered as lead compounds for further optimization to obtain novel medicines that might be used as components of complex ALS therapy.

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Low Level of Expression of C-Terminally Truncated Human FUS Causes Extensive Changes in the Spinal Cord Transcriptome of Asymptomatic Transgenic Mice

Cited by 4 publications

References 54 publications

Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration

Behavioural impairments in mice of a novel FUS transgenic line recapitulate features of frontotemporal lobar degeneration

Abl kinase-mediated FUS Tyr526 phosphorylation alters nucleocytoplasmic FUS localization in FTLD-FUS

A bioisostere of Dimebon/Latrepirdine delays the onset and slows the progression of pathology in FUS transgenic mice

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