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Our study on a mouse carrying a catalytically inactive version of the RNA kinase CLP1, a component of the tRNA splicing endonuclease complex, revealed a neurological disorder characterized by progressive loss of lower spinal motor neurons. Surprisingly, mutant mice accumulate a novel class of tRNA\u2010derived fragments. In addition, patients with homozygous missense mutations in CLP1 (R140H) were recently identified who suffer from severe motor\u2010sensory defects, cortical dysgenesis and microcephaly, and exhibit alterations in transfer RNA (tRNA) splicing. Here, we review functions of CLP1 in different RNA pathways and provide hypotheses on the role of the tRNA splicing machinery in the generation of tRNA fragments and the molecular links to neurodegenerative disorders. We further immerse the biology of tRNA splicing into topics of (t)RNA metabolism and oxidative stress, putting forward the idea that defects in tRNA processing leading to tRNA fragment accumulation might trigger the development of neurodegenerative diseases. <jats:italic>WIREs RNA<\/jats:italic> 2015, 6:47\u201363. doi: 10.1002\/wrna.1255<\/jats:p><jats:p>This article is categorized under:\n<jats:list list-type=\"explicit-label\">\n<jats:list-item><jats:p>RNA Processing &gt; 3' End Processing<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>RNA Processing &gt; tRNA Processing<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>RNA in Disease and Development &gt; RNA in Disease<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p>","DOI":"10.1002\/wrna.1255","type":"journal-article","created":{"date-parts":[[2014,8,20]],"date-time":"2014-08-20T14:59:20Z","timestamp":1408546760000},"page":"47-63","source":"Crossref","is-referenced-by-count":54,"title":["<scp>CLP1<\/scp> as a novel 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