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There is no cure or treatment available that can prevent or reverse neurodegenerative conditions. The causes of neurodegeneration in these diseases remain largely unknown; yet, an extremely small proportion of these devastating diseases are associated with genetic mutations in proteins involved in a wide range of cellular pathways and processes. Over the past decade, it has become increasingly clear that the most notable neurodegenerative diseases, such as ALS, FTLD, and AD, share a common prominent pathological feature known as TAR DNA\u2010binding protein 43 (TDP\u201043) proteinopathy, which is usually characterized by the presence of aberrant phosphorylation, ubiquitination, cleavage and\/or nuclear depletion of TDP\u201043 in neurons and glial cells. The role of TDP\u201043 as a neurotoxicity trigger has been well documented in different <jats:italic>in\u00a0vitro<\/jats:italic> and <jats:italic>in\u00a0vivo<\/jats:italic> experimental models. As such, the investigation of TDP\u201043 pathomechanisms in various major neurodegenerative diseases is on the rise. Here, after a discussion of stages of TDP\u201043 proteinopathy during disease progression in various major neurodegenerative diseases, we review previous and most recent studies about the potential pathomechanisms with a particular emphasis on ALS, FTLD, and AD, and discuss the possibility of targeting TDP\u201043 as a common therapeutic approach to treat neurodegenerative diseases.<\/jats:p><\/jats:sec><jats:sec><jats:label\/><jats:p>\n<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\/jnc14327-fig-0002-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text>\n<\/jats:p><\/jats:sec>","DOI":"10.1111\/jnc.14327","type":"journal-article","created":{"date-parts":[[2018,2,27]],"date-time":"2018-02-27T18:42:59Z","timestamp":1519756979000},"page":"7-20","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":220,"title":["Pathomechanisms of TDP\u201043 in neurodegeneration"],"prefix":"10.1111","volume":"146","author":[{"given":"Ju","family":"Gao","sequence":"first","affiliation":[{"name":"Departments of Pathology Case Western Reserve University Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luwen","family":"Wang","sequence":"additional","affiliation":[{"name":"Departments of Pathology Case Western Reserve University Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikayla 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