Localization of fused in sarcoma (FUS) protein to the post-synaptic density in the brain

Aoki, Naoya; Higashi, Shinji; Kawakami, Ito; Kobayashi, Zen; Hosokawa, Masato; Katsuse, Omi; Togo, Takashi; Hirayasu, Yoshio; Akiyama, Haruhiko

doi:10.1007/s00401-012-0984-6

Cited by 38 publications

(38 citation statements)

References 42 publications

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“…The physiological relevance of Y526 phosphorylation still needs to be elucidated, but it is possible that the phosphorylation of Y526 serves to enhance the dissociation of FUS from TNPO1 once it has been transported into the nucleus. By contrast, phosphorylated Y526 could also prevent a portion of the FUS protein from entering the nucleus in order to fulfil its cytoplasmic functions, where it plays a role in the transport of mRNA to dendritic spines (Belly et al, 2005;Aoki et al, 2012).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of C-terminal tyrosine 526 in FUS impairs its nuclear import

Darovic

Mihevc

Župunski

et al. 2015

Journal of Cell Science

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Aberrant cytoplasmic aggregation of FUS, which is caused by mutations primarily in the C-terminal nuclear localisation signal, is associated with 3% of cases of familial amyotrophic lateral sclerosis (ALS). FUS aggregates are also pathognomonic for 10% of all frontotemporal lobar degeneration (FTLD) cases; however, these cases are not associated with mutations in the gene encoding FUS. This suggests that there are differences in the mechanisms that drive inclusion formation of FUS in ALS and FTLD. Here, we show that the C-terminal tyrosine residue at position 526 of FUS is crucial for normal nuclear import. This tyrosine is subjected to phosphorylation, which reduces interaction with transportin 1 and might consequentially affect the transport of FUS into the nucleus. Furthermore, we show that this phosphorylation can occur through the activity of the Src family of kinases. Our study implicates phosphorylation as an additional mechanism by which nuclear transport of FUS might be regulated and potentially perturbed in ALS and FTLD.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of C-terminal tyrosine 526 in FUS impairs its nuclear import

Darovic

Mihevc

Župunski

et al. 2015

Journal of Cell Science

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“…The cryocut sections of 30 μm thickness were used for the high sensitive, free-floating immunhistochemical staining [23]. The antibodies used in this study are listed in Additional file 1: Table S1.…”

Section: Methodsmentioning

confidence: 99%

Tau accumulation in the nucleus accumbens in tangle-predominant dementia

Kawakami

Hasegawa

Arai

et al. 2014

acta neuropathol commun

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BackgroundTangle-predominant dementia (TPD) is characterized neuropathologically by numerous neurofibrillary tangles in the limbic areas with no or occasional senile plaques throughout the brain. TPD is an under-recognized disease, while it is a common cause of dementia in those over 80 years of age. In the present study, we describe hyperphosphorylated tau (tau) accumulation in the nucleus accumbens (Acb) in patients with TPD.ResultsWe investigated immunohistochemically the brain tissues from 7 patients with TPD, 22 with Alzheimer disease (AD) and 11 non-demented aged subjects. In the Acb of all 7 TPD patients, a considerable number of tau positive neurons were found together with many neuropil threads. The tau deposits in the Acb were labeled with all the anti-tau antibodies used in the present study. They included conformational change-specific, phosphorylation-specific and phosphorylation-independent antibodies. The Acb consists of the predominant medium-sized neurons with a small number of large neurons. Both the cell types were affected by tau pathology in TPD. Tau accumulation in the majority of such neurons appeared to be pretangle-like, diffuse deposits with only occasional paired helical filament formation. Tau positive neurons were also found in the Acb in some AD and non-demented aged subjects but much fewer in the majority of cases. The immunoblot analyses of fresh frozen samples of the Acb and parahippocampal cortex from 3 TPD and 3 AD patients revealed that the insoluble tau in the Acb was a mixture of the 3- and 4-repeat isoforms.ConclusionsTo our knowledge, this is the first report on the occurrence of tau accumulation in the Acb in TPD. The Acb receives direct and massive projections from the hippocampal CA1 and subiculum where neurofibrillary tangles are known to occur more frequently in TPD than in AD. The prevalence of abnormal tau accumulation in the Acb in TPD may support the idea that abnormal tau aggregation propagates via neural circuits. In all but one TPD cases used in this study, delusion was a consistent clinical feature. Whether the Acb tau accumulation is related to the psychiatric symptoms in TPD may be an issue for further investigation.

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“…Interestingly, FUS appears to be able to directly associate with the postsynaptic density (PSD) in an activity dependent manner [398,399]. In response to glutamate activation, FUS accumulates in the dendrites along with increased RNA content that include among others Nd1-L ( Ivns1abp ), an actin-stabilization protein, ActB and Snap25 mRNAs [400,401,402].…”

Section: Late-onset Neurodegenerationmentioning

confidence: 99%

Unraveling the Pathways to Neuronal Homeostasis and Disease: Mechanistic Insights into the Role of RNA-Binding Proteins and Associated Factors

Ravanidis

Kattan

Doxakis

2018

IJMS

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The timing, dosage and location of gene expression are fundamental determinants of brain architectural complexity. In neurons, this is, primarily, achieved by specific sets of trans-acting RNA-binding proteins (RBPs) and their associated factors that bind to specific cis elements throughout the RNA sequence to regulate splicing, polyadenylation, stability, transport and localized translation at both axons and dendrites. Not surprisingly, misregulation of RBP expression or disruption of its function due to mutations or sequestration into nuclear or cytoplasmic inclusions have been linked to the pathogenesis of several neuropsychiatric and neurodegenerative disorders such as fragile-X syndrome, autism spectrum disorders, spinal muscular atrophy, amyotrophic lateral sclerosis and frontotemporal dementia. This review discusses the roles of Pumilio, Staufen, IGF2BP, FMRP, Sam68, CPEB, NOVA, ELAVL, SMN, TDP43, FUS, TAF15, and TIA1/TIAR in RNA metabolism by analyzing their specific molecular and cellular function, the neurological symptoms associated with their perturbation, and their axodendritic transport/localization along with their target mRNAs as part of larger macromolecular complexes termed ribonucleoprotein (RNP) granules.

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Localization of fused in sarcoma (FUS) protein to the post-synaptic density in the brain

Cited by 38 publications

References 42 publications

Phosphorylation of C-terminal tyrosine 526 in FUS impairs its nuclear import

Phosphorylation of C-terminal tyrosine 526 in FUS impairs its nuclear import

Tau accumulation in the nucleus accumbens in tangle-predominant dementia

Unraveling the Pathways to Neuronal Homeostasis and Disease: Mechanistic Insights into the Role of RNA-Binding Proteins and Associated Factors

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