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To be fully active, tRNAs undergo extensive post-transcriptional modifications, catalyzed by different tRNA-modifying enzymes. Lack of these modifications increases the level of missense errors and affects codon decoding rate, contributing to protein aggregation with deleterious consequences to the cell. Recent works show that tRNA hypomodification and tRNA-modifying-enzyme deregulation occur in several diseases where proteostasis is affected, namely, neurodegenerative and metabolic diseases. In this review, we discuss the recent findings that correlate aberrant tRNA modification with proteostasis imbalances, in particular in neurological and metabolic disorders, and highlight the association between tRNAs, their modifying enzymes, translational decoding, and disease onset.<\/jats:p>","DOI":"10.3390\/ijms19123738","type":"journal-article","created":{"date-parts":[[2018,11,26]],"date-time":"2018-11-26T03:24:27Z","timestamp":1543202667000},"page":"3738","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":110,"title":["Impact of tRNA Modifications and tRNA-Modifying Enzymes on Proteostasis and Human Disease"],"prefix":"10.3390","volume":"19","author":[{"given":"Marisa","family":"Pereira","sequence":"first","affiliation":[{"name":"Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, 3810 Aveiro, Portugal"}]},{"given":"Stephany","family":"Francisco","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, 3810 Aveiro, Portugal"}]},{"given":"Ana Sofia","family":"Varanda","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, 3810 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8102-3287","authenticated-orcid":false,"given":"Mafalda","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, 3810 Aveiro, Portugal"}]},{"given":"Manuel A. S.","family":"Santos","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, 3810 Aveiro, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4000-7461","authenticated-orcid":false,"given":"Ana Raquel","family":"Soares","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, 3810 Aveiro, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2018,11,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1832","DOI":"10.1101\/gad.1956510","article-title":"tRNA biology charges to the front","volume":"24","author":"Phizicky","year":"2010","journal-title":"Genes Dev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"D184","DOI":"10.1093\/nar\/gkv1309","article-title":"GtRNAdb 2.0: An expanded database of transfer RNA genes identified in complete and draft genomes","volume":"44","author":"Chan","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1016\/S0022-2836(66)80022-0","article-title":"Codon\u2014Anticodon pairing: The wobble hypothesis","volume":"19","author":"Crick","year":"1966","journal-title":"J. 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