{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T10:57:55Z","timestamp":1764413875461,"version":"3.40.5"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T00:00:00Z","timestamp":1642032000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Neuropathology"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:p>Fukutin, a product of the causative gene of Fukuyama congenital muscular dystrophy (FCMD), is known to be responsible for basement membrane formation. Patients with FCMD exhibit not only muscular dystrophy but also central nervous system abnormalities, including polymicrogyria and neurofibrillary tangles (NFTs) in the cerebral cortex. The formation of NFTs cannot be explained by basement membrane disorganization. To determine the involvement of fukutin in the NFT formation, we performed molecular pathological investigations using autopsied human brains and cultured neurons of a cell line (SH\u2010SY5Y). In human brains, NFTs, identified with an antibody against phosphorylated tau (p\u2010tau), were observed in FCMD patients but not age\u2010matched control subjects and were localized in cortical neurons lacking somatic immunoreactivity for glutamic acid decarboxylase (GAD), a marker of inhibitory neurons. In FCMD brains, NFTs were mainly distributed in lesions of polymicrogyria. Immunofluorescence staining revealed the colocalization of immunoreactivities for p\u2010tau and phosphorylated glycogen synthase kinase\u20103\u03b2 (GSK\u20103\u03b2), a potential tau kinase, in the somatic cytoplasm of SH\u2010SY5Y cells; both the immunoreactivities were increased by <jats:italic>fukutin<\/jats:italic> knockdown and reduced by <jats:italic>fukutin<\/jats:italic> overexpression. Western blot analysis using SH\u2010SY5Y cells revealed consistent results. Enzyme\u2010linked immunosorbent assay (ELISA) confirmed the binding affinity of fukutin to tau and GSK\u20103\u03b2 in SH\u2010SY5Y cells. In the human brains, the density of GAD\u2010immunoreactive neurons in the frontal cortex was significantly higher in the FCMD group than in the control group. GAD immunoreactivity on Western blots of SH\u2010SY5Y cells was significantly increased by <jats:italic>fukutin<\/jats:italic> knockdown. On immunofluorescence staining, immunoreactivities for fukutin and GAD were colocalized in the somatic cytoplasm of the human brains and SH\u2010SY5Y cells, whereas those for fukutin and synaptophysin were colocalized in the neuropil of the human brains and the cytoplasm of SH\u2010SY5Y cells. ELISA confirmed the binding affinity of fukutin to GAD and synaptophysin in SH\u2010SY5Y cells. The present results provide <jats:italic>in vivo<\/jats:italic> and <jats:italic>in vitro<\/jats:italic> evidence for novel properties of fukutin as follows: (i) there is an inverse relationship between fukutin expression and GSK\u20103\u03b2\/tau phosphorylation in neurons; (ii) fukutin binds to GSK\u20103\u03b2 and tau; (iii) tau phosphorylation occurs in non\u2010GAD\u2010immunoreactive neurons in FCMD brains; (iv) neuronal GAD expression is upregulated in the absence of fukutin; and (v) fukutin binds to GAD and synaptophysin in presynaptic vesicles of neurons.<\/jats:p>","DOI":"10.1111\/neup.12797","type":"journal-article","created":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T23:46:30Z","timestamp":1642117590000},"page":"28-39","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Fukutin regulates tau phosphorylation and synaptic function: Novel properties of fukutin in neurons"],"prefix":"10.1111","volume":"42","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6580-557X","authenticated-orcid":false,"given":"Ryota","family":"Tsukui","sequence":"first","affiliation":[{"name":"Graduate School of Medicine Tokyo Women's Medical University  Tokyo Japan"},{"name":"Division of Human Pathology &amp; Pathological Neuroscience, Department of Pathology Tokyo Women's Medical University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomoko","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Division of Human Pathology &amp; Pathological Neuroscience, Department of Pathology Tokyo Women's Medical University  Tokyo Japan"},{"name":"Department of Surgical Pathology Tokyo Women's Medical University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukinori","family":"Okamura","sequence":"additional","affiliation":[{"name":"Graduate School of Medicine Tokyo Women's Medical University  Tokyo Japan"},{"name":"Division of Human Pathology &amp; Pathological Neuroscience, Department of Pathology Tokyo Women's Medical University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0777-5020","authenticated-orcid":false,"given":"Yoichiro","family":"Kato","sequence":"additional","affiliation":[{"name":"Division of Human Pathology &amp; Pathological Neuroscience, Department of Pathology Tokyo Women's Medical University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7173-5061","authenticated-orcid":false,"given":"Noriyuki","family":"Shibata","sequence":"additional","affiliation":[{"name":"Division of Human Pathology &amp; Pathological Neuroscience, Department of Pathology Tokyo Women's Medical University  Tokyo Japan"},{"name":"Department of Surgical Pathology Tokyo Women's Medical University  Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,1,13]]},"reference":[{"key":"e_1_2_7_2_1","first-page":"5","article-title":"A peculiar from of congenital progressive muscular dystrophy. 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