Non-nuclear Pool of Splicing Factor SFPQ Regulates Axonal Transcripts Required for Normal Motor Development

Thomas-Jinu, Swapna; Gordon, Patricia M.; Fielding, Triona; Taylor, Richard; Smith, Bradley N.; Snowden, Victoria; Blanc, Eric; Vance, Caroline; Topp, Simon; Wong, Chun Hao; Bielen, Holger; Williams, Kelly L.; McCann, Emma; Nicholson, Garth A.; Pan-Vazquez, Alejandro; Fox, Archa; Bond, Charles S.; Talbot, William S.; Blair, Ian P.; Shaw, Christopher E.; Houart, Corinne

doi:10.1016/j.neuron.2017.04.036

Cited by 37 publications

(61 citation statements)

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“…Due to these essential functions, dysregulation of SFPQ is predicted to have wide-ranging downstream effects. Indeed, loss of SFPQ function is associated with embryonic death in mice and zebrafish (16,35,36). In this study, we 0 characterised SFPQ pathology in ALS patients and identified novel and rare SFPQ gene variants in SALS cases.…”

Section: Sfpq Positive Aggregates In Als Patient Neuronsmentioning

confidence: 94%

“…Genetic variation in SFPQ has been linked to ALS through the identification of two novel sequence variants in SFPQ in FALS patients (16) located in adjacent amino acids within a domain responsible for SFPQ localisation, paraspeckle formation and transcriptional regulation (17). Neither variant was able to rescue motor neuron deficits in a SFPQ null mutant zebrafish model, suggesting an impairment of SFPQ function (16). However, segregation with disease could not be tested in either case, thus a definitive causal link between the variants and ALS is yet to be established.…”

Section: Introductionmentioning

confidence: 99%

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SFPQ intron retention, reduced expression and aggregate formation in central nervous system tissue are pathological features of amyotrophic lateral sclerosis

Hogan

Grima

Fifita

et al. 2020

Preprint

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Background: Splicing factor proline and glutamine rich (SFPQ, also known as polypyrimidine tract-binding protein-associated-splicing factor, PSF) is a RNA-DNA binding protein with roles in key cellular pathways such as DNA transcription and repair, RNA processing and paraspeckle formation. Dysregulation of SFPQ is emerging as a common pathological feature of multiple neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). Increased retention of SFPQ intron nine and nuclear loss of the protein have been linked to multiple genetic subtypes of ALS. Consequently, SFPQ dysregulation has been hypothesised to be a common pathological feature of this highly heterogeneous disease. Methods: This study provides a comprehensive assessment of SFPQ pathology in large ALS patient cohorts. SFPQ gene expression and intron nine retention were examined in multiple neuroanatomical regions and blood from ALS patients and control individuals using RNA sequencing (RNA-Seq) and quantitative PCR (RT-qPCR). SFPQ protein levels were assessed by immunoblotting of patient and control motor cortex and SFPQ expression pattern was examined by immunofluorescent staining of patient and control spinal cord sections. Finally, whole-genome sequencing data from a large cohort of sporadic ALS patients was analysed for genetic variation in SFPQ. Results: SFPQ intron nine retention was significantly increased in ALS patient motor cortex. Total SFPQ mRNA expression was significantly downregulated in ALS patient motor cortex but not ALS patient blood, indicating tissue specific SFPQ dysregulation. At the protein level, nuclear expression of SFPQ in both control and patient spinal motor neurons was highly variable and nuclear depletion of SFPQ was not a consistent feature in our ALS cohort. However, we did observe SFPQ-positive cytoplasmic ubiquitinated protein aggregates in ALS spinal motor neurons. In addition, our genetic screen of ALS patients identified two novel, and two rare sequence variants in SFPQ not previously reported in ALS. Conclusions: This study shows that dysregulation of SFPQ is a feature of ALS patient central nervous system tissue. These findings confirm SFPQ pathology as a feature of ALS and indicate that investigations into the functional consequences of this pathology will provide insight into the biology of ALS.

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Section: Sfpq Positive Aggregates In Als Patient Neuronsmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

SFPQ intron retention, reduced expression and aggregate formation in central nervous system tissue are pathological features of amyotrophic lateral sclerosis

Hogan

Grima

Fifita

et al. 2020

Preprint

Self Cite

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“…Nuclear loss of the PSF protein in ALS transgenic mouse models and the spinal cord of human postmortem cases with sporadic ALS was observed, indicating that this event is a molecular hallmark of ALS (Luisier et al, ). Another report showed that PSF localized to the motor axons and promoted motor neuron differentiation (Thomas‐Jinu et al, ). Previous analysis of human AD/FTD brain tissues and the dysregulated expression in a mouse model revealed the occurrence of a dysregulation in the PSF protein activity (Ke et al, ).…”

Section: Discussionmentioning

confidence: 98%

“…PSF encodes a protein involved in multiple roles such as RNA processing, transcriptional regulation and DNA repair contributing to axon viability in the neurons (Thomas‐Jinu et al, ). PSF is localized within the nucleus of structures known as paraspeckles (Yarosh et al, ).…”

Section: Discussionmentioning

confidence: 99%

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

2019

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Amyloid precursor protein (APP) is a representative gene related to Alzheimer's disease (AD). Androgens function by binding to the androgen receptor (AR). Both androgen and RNA‐binding protein PSF play a role in the pathology of AD. However, the involvement of AR and PSF in APP regulation in neuron has not been investigated. Here, we explored the regulatory mechanism of APP expression by AR and PSF using neuron‐derived cells. We demonstrated that androgen up‐regulates the production of APP at the mRNA and protein levels. This induction is enhanced by AR over‐expression and inhibited by its silencing. One candidate AR‐binding region was identified in the intron region of APP and validated its activity as AR‐dependent enhancer by the luciferase assay. Furthermore, the public transcriptome data of brain tissues of mice indicated that APP is regulated by PSF post‐transcriptionally. We observed a decreased expression of APP after PSF knockdown and interaction of PSF with the APP transcript. Moreover, we revealed that silencing of PSF inhibited the stability of the APP mRNA. Thus, these results presented a new regulatory mechanism of APP expression by androgen through AR‐mediated transcription and PSF at the post‐transcriptional level that might be associated with the occurrence of AD.

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“…Ppp1cb is associated with aging and mortality [28]. The second-highest ranked gene that is specific to only the 24-month list is Sfpq, a gene linked to diseases such as familial amyotrophic lateral sclerosis (ALS) [4]. Additionally, mutations in Sfpq and the dysregulation of the Sfpq-dependent energy metabolism may be connected to sarcopenia, also known as biological aging [10].…”

Section: Top Feature Importances Reveal Gene Ontology Patterns By Agementioning

confidence: 99%

Single-cell identity definition using random forests and recursive feature elimination

Park

Vorperian

Wang

et al. 2020

Preprint

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Single cell RNA sequencing (scRNA-seq) enables detailed examination of a cell's underlying regulatory networks and the molecular factors contributing to its identity. We developed scRFE (single-cell identity definition using random forests and recursive feature elimination, pronounced 'surf') with the goal of easily generating interpretable gene lists that can accurately distinguish observations (single-cells) by their features(genes) given a class of interest. scRFE is an algorithm implemented as a Python package that combines the classical random forest method with recursive feature elimination and cross validation to find the features necessary and sufficient to classify cells in a single-cell RNA-seq dataset by ranking feature importance. The package is compatible with Scanpy, enabling a seamless integration into any single-cell data analysis workflow that aims at identifying minimal transcriptional programs relevant to describing metadata features of the dataset. We applied scRFE to the Tabula Muris Senis and reproduced commonly known aging patterns and transcription factor reprogramming protocols, highlighting the biological value of scRFE's learned features.

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Non-nuclear Pool of Splicing Factor SFPQ Regulates Axonal Transcripts Required for Normal Motor Development

Cited by 37 publications

References 0 publications

SFPQ intron retention, reduced expression and aggregate formation in central nervous system tissue are pathological features of amyotrophic lateral sclerosis

SFPQ intron retention, reduced expression and aggregate formation in central nervous system tissue are pathological features of amyotrophic lateral sclerosis

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

Single-cell identity definition using random forests and recursive feature elimination

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