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A hallmark pathological feature of both diseases is the depletion of the RNA\u2010binding protein TDP\u201043 from the nucleus in the brain and spinal cord of patients. A major function of TDP\u201043 is to repress the inclusion of cryptic exons during RNA splicing. When it becomes depleted from the nucleus in disease, this function is lost, and recently, several key cryptic splicing targets of TDP\u201043 have emerged, including <jats:italic>STMN2<\/jats:italic>, <jats:italic>UNC13A<\/jats:italic>, and others. <jats:italic>UNC13A<\/jats:italic> is a major ALS\/FTD risk gene, and the genetic variations that increase the risk for disease seem to do so by making the gene more susceptible to cryptic exon inclusion when TDP\u201043 function is impaired. Here, we discuss the prospects and challenges of harnessing these cryptic splicing events as novel therapeutic targets and biomarkers. Deciphering this new cryptic code may be a touchstone for ALS and FTD diagnosis and treatment.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ctm2.818","type":"journal-article","created":{"date-parts":[[2022,5,12]],"date-time":"2022-05-12T20:09:35Z","timestamp":1652386175000},"source":"Crossref","is-referenced-by-count":31,"title":["Cracking the cryptic code in amyotrophic lateral sclerosis and frontotemporal dementia: Towards therapeutic targets and biomarkers"],"prefix":"10.1002","volume":"12","author":[{"given":"Tetsuya","family":"Akiyama","sequence":"first","affiliation":[{"name":"Department of Genetics Stanford University School of Medicine  Stanford California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Koike","sequence":"additional","affiliation":[{"name":"Department of Neuroscience Mayo Clinic  Jacksonville Florida 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