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Extensive post\u2010translational modifications, especially hyperphosphorylation, and abnormal aggregation of tau protein underlie tauopathy. <jats:italic>Cis\u2013trans<\/jats:italic> isomerization of protein plays an important role in protein folding, function, and degradation, which is regulated by peptidyl\u2010proline isomerases (PPIases). Peptidyl\u2010prolyl cis\u2013trans isomerase NIMA\u2010interacting 1 (Pin1), the only PPIase found to isomerize Pro following phosphorylated Ser or Thr residues, alters phosphorylated tau protein conformation at pT231\u2010P motif. The <jats:italic>cis<\/jats:italic> P\u2010tau but not <jats:italic>trans<\/jats:italic> P\u2010tau serves as an early driver of multiple neurodegenerative disease, encompassing AD, traumatic brain injury (TBI), chronic traumatic encephalopathy (CTE), and vascular contributions to cognitive impairment and dementia (VCID). <jats:italic>Cis<\/jats:italic> but not <jats:italic>trans<\/jats:italic> P\u2010tau is resistant to protein dephosphorylation and degradation, and also prone to protein aggregation. <jats:italic>Cis<\/jats:italic> P\u2010tau loses its ability to stabilize microtubule, causing and spreading tauopathy mainly in axons, a pathological process called cistauosis. The conformation\u2010specific monoclonal antibody that targets only the <jats:italic>cis<\/jats:italic> P\u2010tau serves as a very early diagnosis method and a potential treatment of not only conventional tauopathies but also nonconventional tauopathies such as VCID, with clinical trials ongoing. Notably, <jats:italic>cis<\/jats:italic> P\u2010tau antibody is the only clinical\u2010stage Alzheimer's therapeutic that has shown the efficacy in animal models of not only AD but also TBI and stroke, which are very early stages of dementia. Here we review the identification and pathological consequences of <jats:italic>cis<\/jats:italic> pt231\u2010tau, the role of its regulator Pin1, as well as the clinical implication of <jats:italic>cis<\/jats:italic> pt231\u2010tau conformation\u2010specific antibody in conventional and nonconventional tauopathies.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/jnc15909-fig-0002-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p>","DOI":"10.1111\/jnc.15909","type":"journal-article","created":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T08:28:27Z","timestamp":1693211307000},"page":"904-914","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Function and regulation of <i>cis<\/i> P\u2010tau in the pathogenesis and treatment of conventional and nonconventional tauopathies"],"prefix":"10.1111","volume":"166","author":[{"given":"Ruizhi","family":"Wang","sequence":"first","affiliation":[{"name":"Departments of Biochemistry and Oncology, Schulich School of Medicine &amp; Dentistry Western University  London Ontario Canada"},{"name":"Robarts Research Institute Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0734-1567","authenticated-orcid":false,"given":"Kun Ping","family":"Lu","sequence":"additional","affiliation":[{"name":"Departments of Biochemistry and Oncology, Schulich School of Medicine &amp; Dentistry Western University  London Ontario Canada"},{"name":"Robarts Research Institute Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9309-5659","authenticated-orcid":false,"given":"Xiao 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