Aspects of degradation and translation of the expanded C9orf72 hexanucleotide repeat RNA

An hexanucleotide repeat expansion in the non-cording region ofC9orf72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis. Bidirectional transcription of the repeat region produces sense and antisense expanded repeat containing RNAs. Transcribed repeat RNAs that escape proper degradation may themselves be neurotoxic. Moreover, unconventional translation of residual repeat RNA produces toxic dipeptide repeat proteins, further complicating pathophysiology. Here, we summarize molecular mechanism of degradation and translation of the repeat RNA. Such efforts will contribute to the elucidation of some aspects ofC9orf72-related neurodegeneration and the development of future therapies. AbstractAn hexanucleotide repeat expansion mutation in the non-coding region ofC9orf72 gene causes frontotemporal dementia and amyotrophic lateral sclerosis. This mutation is estimated to be the most frequent genetic cause of these currently incurable diseases. Since the mutation causes autosomal dominantly inherited diseases, disease cascade essentially starts from the expanded DNA repeats. However, molecular disease mechanism is inevitably complex because possible toxic entity for the disease is not just functional loss of translated C9ORF72 protein, if any, but potentially includes bidirectionally transcribed expanded repeat containing RNA and their unconventional repeat-associated non-AUG translation products in all possible reading frames. Although the field learned so much ab...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: REVIEW Source Type: research