Trinucleotide-repeat expansion diseases (TREDs) are a group of inherited human genetic disorders normally involving late-onset neurological/neurodegenerative affectation. Trinucleotide-repeat expansions occur in coding and non-coding regions of unique genes that typically result in protein and RNA toxic gain of function, respectively. In polyglutamine (polyQ) disorders caused by an expanded CAG repeat in the coding region of specific genes, neuronal dysfunction has been traditionally linked to the long polyQ stretch. However, a number of evidences suggest a detrimental role of the expanded/mutant mRNA, which may contribute to cell function impairment. In this review we describe the mechanisms of RNA-induced toxicity in TREDs with special focus in small-non-coding RNA pathogenic mechanisms and we summarize and comment on translational approaches targeting the expanded trinucleotide-repeat for disease modifying therapies.

This work was supported by the Spanish Government and FEDER (Fondo Europeo de Desarrollo Regional): PN de I+D+I 2008-2011 PI081367 and PN de I+D+I 2012-2015 PI11/02036, Instituto Carlos III –ISCIII-, Subdirección General de Evaluación y Fomento de la Investigación (to Eulàlia Martí), SAF2008-00357 Ministerio de Economia y competitividad, ISCIII (to Xavier Estivill). The Spanish Government supports Eulàlia Martí (Programa Miguel Servet).