Splicing factor proline and glutamine rich intron retention, reduced expression and aggregate formation are pathological features of amyotrophic lateral sclerosis. (2nd August 2021)

• Record Type: Journal Article
• Authors: Hogan, Alison L.; Grima, Natalie; Fifita, Jennifer A.; McCann, Emily P.; Heng, Benjamin; Fat, Sandrine Chan Moi; Wu, Sharlynn; Maharjan, Ram; Cain, Amy K.; Henden, Lyndal; Rayner, Stephanie; Tarr, Ingrid; Zhang, Katharine Y.; Zhao, Qiongyi; Zhang, Zong‐Hong; Wright, Amanda; Lee, Albert; Morsch, Marco; Yang, Shu; Williams, Kelly L.; Blair, Ian P.
• Is Part Of: Neuropathology & applied neurobiology. Volume 47:Number 7(2021)
• Page Start: 990
• Page End: 1003
• Publication Date: 2021-08-02
• Subjects: amyotrophic lateral sclerosis -- histopathology -- polypyrimidine tract‐binding protein‐associated splicing factor (PSF) -- protein aggregation -- RNA expression -- RNA processing -- splicing factor proline and glutamine rich (SFPQ); Nervous system -- Diseases -- Pathology -- Periodicals; Nervous system -- Diseases -- Periodicals; 616.8
• DOI: 10.1111/nan.12749
• Languages: English
• ISSNs: 0305-1846

Abstract

Abstract: Aim: Splicing factor proline and glutamine rich (SFPQ) is an RNA–DNA binding protein that is dysregulated in Alzheimer's disease and frontotemporal dementia. Dysregulation of SFPQ, specifically increased intron retention and nuclear depletion, has been linked to several genetic subtypes of amyotrophic lateral sclerosis (ALS), suggesting that SFPQ pathology may be a common feature of this heterogeneous disease. Our study aimed to investigate this hypothesis by providing the first comprehensive assessment of SFPQ pathology in large ALS case–control cohorts. Methods: We examined SFPQ at the RNA, protein and DNA levels. SFPQ RNA expression and intron retention were examined using RNA‐sequencing and quantitative PCR. SFPQ protein expression was assessed by immunoblotting and immunofluorescent staining. At the DNA level, SFPQ was examined for genetic variation novel to ALS patients. Results: At the RNA level, retention of SFPQ intron nine was significantly increased in ALS patients' motor cortex. In addition, SFPQ RNA expression was significantly reduced in the central nervous system, but not blood, of patients. At the protein level, neither nuclear depletion nor reduced expression of SFPQ was found to be a consistent feature of spinal motor neurons. However, SFPQ‐positive ubiquitinated protein aggregates were observed in patients' spinal motor neurons. At the DNA level, our genetic screen identified two novel and two rare SFPQ sequence variants not previously reported in the literature. Conclusions: Our findings confirm dysregulation of SFPQ as a pathological feature of the central nervous system of ALS patients and indicate that investigation of the functional consequences of this pathology will provide insight into ALS biology. Abstract : We present a comprehensive analysis of SPFQ pathology in large ALS patient cohorts. In the central nervous system of ALS patients, we observed dysregulation of SFPQ at the RNA level in the form of reduced expression and increased intron retention. At the protein level, we observed ubiquitinated SFPQ positive aggregates that, at times, colocalised with pTDP‐43. Screening of our large sporadic ALS cohort identified two novel and two rare SFPQ sequence variants in individual patients.