Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD spectrum diseases

Ishigaki, Shinsuke; Riku, Yuichi; Fujioka, Yusuke; Endo, Kanako; Iwade, Nobuyuki; Kawai, Kenichiro; Ishibashi, Minaka; Yokoi, Sana; Katsuno, Masahisa; Watanabe, Haruo; Mori, Keiko; Akagi, Akio; Yokota, Osamu; Terada, Seishi; Kawakami, Ito; Suzuki, Naoki; Warita, Hitoshi; Akiyama, Masashi; Yoshida, Mari; Sobue, Gen

doi:10.1093/brain/awaa196

Cited by 24 publications

(24 citation statements)

References 29 publications

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“…The loss of FUS activity results in the preferential inclusion of exon 10 and an increased expression of 4R tau (100). FUS forms a complex with splicing factor, proline-and glutamine-rich (SFPQ) through an RNA-dependant interaction such that the loss of either FUS or SFPQ results in the preferential expression of 4R tau and an accompanying increase in ptau expression, including pathological tau isoforms (101)(102)(103). The importance of this is highlighted by the finding of reduced interactions between FUS and SFPQ across a broad range of FTLDs, including ALS-FTD (102).…”

Section: Neuropathological and Biochemical Evidence Of Altered Tau Mementioning

confidence: 99%

“…FUS forms a complex with splicing factor, proline-and glutamine-rich (SFPQ) through an RNA-dependant interaction such that the loss of either FUS or SFPQ results in the preferential expression of 4R tau and an accompanying increase in ptau expression, including pathological tau isoforms (101)(102)(103). The importance of this is highlighted by the finding of reduced interactions between FUS and SFPQ across a broad range of FTLDs, including ALS-FTD (102). The recent report of a single atypical case of sporadic ALS manifesting with predominantly upper motor neuron dysfunction with extrapyramidal features who at autopsy demonstrated pyramidal neuron FUS basophilic inclusions that colocalized with AT8 tau immunoreactivity in motor neurons, in addition to a 4R predominant tauopathy, provides support for such a proposed role of FUS in contributing to alterations in tau metabolism in ALS (104).…”

Section: Neuropathological and Biochemical Evidence Of Altered Tau Mementioning

confidence: 99%

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Alterations in Tau Metabolism in ALS and ALS-FTSD

2020

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There is increasing acceptance that amyotrophic lateral sclerosis (ALS), classically considered a neurodegenerative disease affecting almost exclusively motor neurons, is syndromic with both clinical and biological heterogeneity. This is most evident in its association with a broad range of neuropsychological, behavioral, speech and language deficits [collectively termed ALS frontotemporal spectrum disorder (ALS-FTSD)]. Although the most consistent pathology of ALS and ALS-FTSD is a disturbance in TAR DNA binding protein 43 kDa (TDP-43) metabolism, alterations in microtubule-associated tau protein (tau) metabolism can also be observed in ALS-FTSD, most prominently as pathological phosphorylation at Thr175 (pThr175tau). pThr175 has been shown to promote exposure of the phosphatase activating domain (PAD) in the tau N-terminus with the consequent activation of GSK3β mediated phosphorylation at Thr231 (pThr231tau) leading to pathological oligomer formation. This pathological cascade of tau phosphorylation has been observed in chronic traumatic encephalopathy with ALS (CTE-ALS) and in both in vivo and in vitro experimental paradigms, suggesting that it is of critical relevance to the pathobiology of ALS-FTSD. It is also evident that the co-existence of alterations in the metabolism of TDP-43 and tau acts synergistically in a rodent model to exacerbate the pathology of either.

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Section: Neuropathological and Biochemical Evidence Of Altered Tau Mementioning

confidence: 99%

Section: Neuropathological and Biochemical Evidence Of Altered Tau Mementioning

confidence: 99%

Alterations in Tau Metabolism in ALS and ALS-FTSD

2020

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“…Interestingly, this effect was observed in all neurons with nuclear or cytoplasmic SFPQ aggregates. One plausible mechanism may involve the sequestration of an important SFPQ interacting partner FUS, leading to its loss of function and consequently, a deficit in dendritic spine morphogenesis [44][45][46]. Alternatively, overexpression of SFPQ can dysregulate the transcription of long genes, many of which are involved in neuronal development and neurite outgrowth [5].…”

Section: Amparsmentioning

confidence: 99%

Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates that reduce surface AMPA receptor expression in primary neurons

Widagdo

Udagedara

Bhembre

et al. 2022

Preprint

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SFPQ is a nuclear RNA-binding protein that is involved in a wide range of physiological processes including neuronal development and homeostasis. However, the mislocalization and cytoplasmic aggregation of SFPQ are associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). We have previously reported that zinc mediates SFPQ polymerization and promotes the formation of cytoplasmic aggregates in neurons. Here we characterize two familial ALS (fALS)-associated SFPQ variants, which cause amino acid substitutions in the proximity of the SFPQ zinc-coordinating center (N533H and L534I). Both mutants display increased zinc-binding affinities, which can be explained by the presence of a secondary zinc-binding site revealed by the 1.83Å crystal structure of the human SFPQ L534I mutant. Overexpression of these fALS-associated mutants significantly increases the number of SFPQ cytoplasmic aggregates in primary neurons. Although they do not affect the density of dendritic spines, the presence of SFPQ cytoplasmic aggregates causes a marked reduction in the levels of the GluA1, but not the GluA2 subunit of AMPA-type glutamate receptors on the neuronal surface. Taken together, our data demonstrate that fALS-associated mutations enhance the propensity of SFPQ to bind zinc and form aggregates, leading to the dysregulation of AMPA receptor subunit composition, which may contribute to neuronal dysfunction in ALS.

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“…ALS-causing MATR3 mutations have been shown to result in nuclear global mRNA export defects, including the mRNA of TDP-43 and FUS, demonstrating the interconnected network of RBPs and their involvement in ALS [96]. Furthermore, loss of the interaction between SFPQ and FUS has been identified in ALS-FTD [97].…”

Section: Deregulated Rna Metabolismmentioning

confidence: 99%

The Interplay of RNA Binding Proteins, Oxidative Stress and Mitochondrial Dysfunction in ALS

2021

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RNA binding proteins fulfil a wide number of roles in gene expression. Multiple mechanisms of RNA binding protein dysregulation have been implicated in the pathomechanisms of several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Oxidative stress and mitochondrial dysfunction also play important roles in these diseases. In this review, we highlight the mechanistic interplay between RNA binding protein dysregulation, oxidative stress and mitochondrial dysfunction in ALS. We also discuss different potential therapeutic strategies targeting these pathways.

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Aberrant interaction between FUS and SFPQ in neurons in a wide range of FTLD spectrum diseases

Cited by 24 publications

References 29 publications

Alterations in Tau Metabolism in ALS and ALS-FTSD

Alterations in Tau Metabolism in ALS and ALS-FTSD

Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates that reduce surface AMPA receptor expression in primary neurons

The Interplay of RNA Binding Proteins, Oxidative Stress and Mitochondrial Dysfunction in ALS

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