Amyloid precursor protein, an androgen‐regulated gene, is targeted by RNA‐binding protein PSF/SFPQ in neuronal cells

Takayama, Ken‐ichi; Fujiwara, Kyoko; Inoue, Satoshi

doi:10.1111/gtc.12721

Cited by 12 publications

(14 citation statements)

References 59 publications

(102 reference statements)

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“…A drastic reduction in SFPQ levels at late stage (12mpi) in 3xTg mice-in corroboration with reduced expression of SFPQ in post-mortem brains of both rapidly progressing diseases (rpAD and prion diseases); indicates that SFPQ could be of potential relevance to identify rapidly progressing forms of dementia. SFPQ reduction (knock down) leads to a decreased expression of amyloid precursor protein (APP) [77] in neuronal cells. Given the presence of extensive Aβ and tau pathology by 12 mpi and tau dependent reduction in SFPQ levels in our cellular study, indicates this reduction as a combinatorial effect of Aβ and tau pathology.…”

Section: Discussionmentioning

confidence: 99%

SFPQ and Tau: critical factors contributing to rapid progression of Alzheimer’s disease

et al. 2020

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Dysfunctional RNA-binding proteins (RBPs) have been implicated in several neurodegenerative disorders. Recently, this paradigm of RBPs has been extended to pathophysiology of Alzheimer's disease (AD). Here, we identified disease subtype specific variations in the RNA-binding proteome (RBPome) of sporadic AD (spAD), rapidly progressive AD (rpAD), and sporadic Creutzfeldt Jakob disease (sCJD), as well as control cases using RNA pull-down assay in combination with proteomics. We show that one of these identified proteins, splicing factor proline and glutamine rich (SFPQ), is downregulated in the post-mortem brains of rapidly progressive AD patients, sCJD patients and 3xTg mice brain at terminal stage of the disease. In contrast, the expression of SFPQ was elevated at early stage of the disease in the 3xTg mice, and in vitro after oxidative stress stimuli. Strikingly, in rpAD patients' brains SFPQ showed a significant dislocation from the nucleus and cytoplasmic colocalization with TIA-1. Furthermore, in rpAD brain lesions, SFPQ and p-tau showed extranuclear colocalization. Of note, association between SFPQ and tau-oligomers in rpAD brains suggests a possible role of SFPQ in oligomerization and subsequent misfolding of tau protein. In line with the findings from the human brain, our in vitro study showed that SFPQ is recruited into TIA-1-positive stress granules (SGs) after oxidative stress induction, and colocalizes with tau/p-tau in these granules, providing a possible mechanism of SFPQ dislocation through pathological SGs. Furthermore, the expression of human tau in vitro induced significant downregulation of SFPQ, suggesting a causal role of tau in the downregulation of SFPQ. The findings from the current study indicate that the dysregulation and dislocation of SFPQ, the subsequent DNArelated anomalies and aberrant dynamics of SGs in association with pathological tau represents a critical pathway which contributes to rapid progression of AD.

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Section: Discussionmentioning

confidence: 99%

SFPQ and Tau: critical factors contributing to rapid progression of Alzheimer’s disease

et al. 2020

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“…After ligand binding, the AR homodimer translocates into the nucleus, where it binds to the androgen-responsive element (ARE), and subsequently activates gene expression often with epigenetic changes in the chromatin state ( Tewari et al, 2012 ; Nevedomskaya et al, 2016 ; Nadal et al, 2017 ; Stelloo et al, 2019 ). APP is a primary androgen-regulated gene in human neuronal and prostate cancer cells ( Takayama et al, 2009 ; Takayama et al, 2019 ). In neurons, AR directly binds to the ARE located within the genomic regions corresponding to the 15th intron of the APP gene ( Takayama et al, 2019 ) ( Figure 1A and Table 1 ).…”

Section: Transcriptional Regulation Of Appmentioning

confidence: 99%

“…APP is a primary androgen-regulated gene in human neuronal and prostate cancer cells ( Takayama et al, 2009 ; Takayama et al, 2019 ). In neurons, AR directly binds to the ARE located within the genomic regions corresponding to the 15th intron of the APP gene ( Takayama et al, 2019 ) ( Figure 1A and Table 1 ). Notably, the chromatin binding level of histone H3 acetylated at lysine 9 (H3K9ac), a transcriptionally active histone mark, at the APP promoter is enhanced with overexpression of AR.…”

Section: Transcriptional Regulation Of Appmentioning

confidence: 99%

“…Importantly, PSF/SFPQ plays a critical role in neural development as well as in neurodegenerative diseases, including AD ( Ke et al, 2012 ; Lu et al, 2018 ; Younas et al, 2020 ). It directly binds to the primary APP transcripts in human neuronal cells, leading to APP mRNA stabilization ( Takayama et al, 2019 ) ( Figure 1B and Table 1 ).…”

Section: Post-transcriptional Regulation Of Appmentioning

confidence: 99%

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Transcriptional and Post-Transcriptional Regulations of Amyloid-β Precursor Protein (APP) mRNA

et al. 2021

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Alzheimer’s disease (AD) is an age-associated neurodegenerative disorder characterized by progressive impairment of memory, thinking, behavior, and dementia. Based on ample evidence showing neurotoxicity of amyloid-β (Aβ) aggregates in AD, proteolytically derived from amyloid precursor protein (APP), it has been assumed that misfolding of Aβ plays a crucial role in the AD pathogenesis. Additionally, extra copies of the APP gene caused by chromosomal duplication in patients with Down syndrome can promote AD pathogenesis, indicating the pathological involvement of the APP gene dose in AD. Furthermore, increased APP expression due to locus duplication and promoter mutation of APP has been found in familial AD. Given this background, we aimed to summarize the mechanism underlying the upregulation of APP expression levels from a cutting-edge perspective. We first reviewed the literature relevant to this issue, specifically focusing on the transcriptional regulation of APP by transcription factors that bind to the promoter/enhancer regions. APP expression is also regulated by growth factors, cytokines, and hormone, such as androgen. We further evaluated the possible involvement of post-transcriptional regulators of APP in AD pathogenesis, such as RNA splicing factors. Indeed, alternative splicing isoforms of APP are proposed to be involved in the increased production of Aβ. Moreover, non-coding RNAs, including microRNAs, post-transcriptionally regulate the APP expression. Collectively, elucidation of the novel mechanisms underlying the upregulation of APP would lead to the development of clinical diagnosis and treatment of AD.

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“…The SFPQ protein is conserved across species and plays a key role in neuronal development and network organization (Thomas-Jinu et al, 2017). The protein structure contains tandem RNA recognition motif domains, a NOPS domain, a coiled-coil region and an N-terminal proline/glutamine-rich low-complexity region (Passon et al, 2012).. More recently, loss of SFPQ function has been implicated as a risk factor for human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), fronto-temporal dementia (FTD) and Alzheimer's Disease (AD) (Ishigaki et al, 2017;Luisier et al, 2018;Takayama et al, 2019;Thomas-Jinu et al, 2017) in mouse, iPSC, and zebrafish models.…”

Section: Introductionmentioning

confidence: 99%

Human patient SFPQ homozygous mutation is found deleterious for brain and motor development in a zebrafish model

Gordon

Efthymiou

Salpietro

et al. 2020

Preprint

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SFPQ (Splicing factor proline-and glutamine-rich) is a DNA and RNA binding protein involved in transcription, pre-mRNA splicing, and DNA damage repair and it has been previously implicated in neurodegenerative disorders. A homozygous p.Ser660Asn variant in SFPQ was identified through whole exome sequencing (WES) in an Italian woman presented a complex neurological phenotype with intellectual disability, peripheral neuropathy, bradykinesia, extrapyramidal rigidity and rest (heads) tremor and neuroradiological anomalies including thin dysplastic corpus callosum, hypomyelination and hypointensity of the globus pallidus and of the mesencephalic substantia nigra (resembling neurodegeneration with brain iron accumulation; NBIA). Using a zebrafish SFPQ genetic model we have showed that a rescue with this SFPQ S660N mutant revealed robust defects in the developing central nervous system (CNS) of the embryos, including abnormal branching of the motor axons innervating body muscles and misfolding of the posterior brain neuroepithelium. The defects hereby identified in the model organism indicate a potential contribution of the homozygous SFPQ p.Ser660Asn variant in some of the patient's neurodegenerative features, including the clinical parkinsonism and the NBIA-like pattern on brain imaging.

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Amyloid precursor protein, an androgen‐regulated gene, is targeted by RNA‐binding protein PSF/SFPQ in neuronal cells

Cited by 12 publications

References 59 publications

SFPQ and Tau: critical factors contributing to rapid progression of Alzheimer’s disease

SFPQ and Tau: critical factors contributing to rapid progression of Alzheimer’s disease

Transcriptional and Post-Transcriptional Regulations of Amyloid-β Precursor Protein (APP) mRNA

Human patient SFPQ homozygous mutation is found deleterious for brain and motor development in a zebrafish model

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