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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\u2013control cohorts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We examined SFPQ at the RNA, protein and DNA levels.\n                      <jats:italic>SFPQ<\/jats:italic>\n                      RNA expression and intron retention were examined using RNA\u2010sequencing and quantitative PCR. SFPQ protein expression was assessed by immunoblotting and immunofluorescent staining. At the DNA level,\n                      <jats:italic>SFPQ<\/jats:italic>\n                      was examined for genetic variation novel to ALS patients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      At the RNA level, retention of\n                      <jats:italic>SFPQ<\/jats:italic>\n                      intron nine was significantly increased in ALS patients' motor cortex. In addition,\n                      <jats:italic>SFPQ<\/jats:italic>\n                      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\u2010positive ubiquitinated protein aggregates were observed in patients' spinal motor neurons. At the DNA level, our genetic screen identified two novel and two rare\n                      <jats:italic>SFPQ<\/jats:italic>\n                      sequence variants not previously reported in the literature.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/nan.12749","type":"journal-article","created":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T02:16:24Z","timestamp":1626833784000},"page":"990-1003","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Splicing factor proline and glutamine rich intron retention, reduced expression and aggregate formation are pathological features of amyotrophic lateral sclerosis"],"prefix":"10.1111","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5987-0639","authenticated-orcid":false,"given":"Alison L.","family":"Hogan","sequence":"first","affiliation":[{"name":"Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie","family":"Grima","sequence":"additional","affiliation":[{"name":"Centre for Motor Neuron Disease Research, Department of Biomedical Sciences, Faculty of Medicine, Health and Human Sciences Macquarie University  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer A.","family":"Fifita","sequence":"additional","affiliation":[{"name":"Centre for Motor Neuron 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