Abstract
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.
Highlights
In the human genome trinucleotide repeats (TNR) are especially abundant in intergenic regions, gene introns and untranslated regions, and translated segments of protein coding genes
We address the possible relevance of bidirectional transcritption in trinucleotide repeat expansion diseases (TREDs) loci and further discuss about the role of small non-coding RNAs in TREDs pathogenesis
Hundreds of mRNA targets could exist per miRNA family and at least 30% of the mRNAs are targeted by miRNAs (O’Carroll and Schaefer, 2013)
Summary
In the human genome trinucleotide repeats (TNR) are especially abundant in intergenic regions, gene introns and untranslated regions, and translated segments of protein coding genes. The largest group of inherited polyglutamine (polyQ) disorders is caused by expansions of CAG repeats in the open reading frame (ORF) of unique genes, including the Huntington’s disease (HD) genes and several spinocerebellar ataxias (SCA) genes. In these diseases the predominant hypothesis has been that the expanded polyQ track confers detrimental properties to the protein, that compromise cell homeostasis. A similar phenomenon has Frontiers in Molecular Neuroscience www.frontiersin.org
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