Models and mechanisms of repeat expansion disorders: a worm’s eye view

Abstract

The inappropriate genetic expansion of various repetitive DNA sequences underlies over 20 distinct inherited diseases. The genetic context of these repeats in exons, introns and untranslated regions has played a major role in thinking about the mechanisms by which various repeat expansions might cause disease. Repeat expansions in exons are thought to give rise to expanded toxic protein repeats (i.e. polyQ). Repeat expansions in introns and UTRs (i.e. FXTAS) are thought to produce aberrant repeat-bearing RNAs that interact with and sequester a wide variety of essential proteins, resulting in cellular toxicity. However, a new phenomenon termed 'repeat-associated nonAUG dependent (RAN) translation' paints a new and unifying picture of how distinct repeat expansion-bearing RNAs might act as substrates for this noncanonical form of translation, leading to the production of a wide range of repeat sequence-specific-encoded toxic proteins. Here, we review how the model system has been utilized to model many repeat disorders and discuss how RAN translation could be a previously unappreciated contributor to the toxicity associated with these different models.

An apparent core/shell architecture of polyQ aggregates in the aging Caenorhabditis elegans neuron

“…C. elegans provides an excellent model for protein aggregation diseases, including HD, 22 with a simple yet fully mapped nervous system, and a short lifespan ideal for studying diseases sensitive to aging. Aggregation of polyQ tracts in the muscle tissue of C. elegans has been demonstrated to be length‐dependent and correlated with toxicity 23,24 .…”

Gene editing and its applications in biomedicine

“…A high-fidelity Cas enzyme to perfectly distinguish one-nucleotide difference between the wild-type and gain-of-function mutant allele is highly desired for this application. Nevertheless, this strategy is helpless when facing some complicated mutation types, for example, the expansion of repeated sequences (Rodriguez and Todd, 2019;Rudich and Lamitina, 2018). It seems that this problem may be addressed by RNA editing (Batra et al, 2017), as unproportioned RNA knockdown of transcripts from the two alleles can be accepted.…”

Reactive Species in Huntington Disease: Are They Really the Radicals You Want to Catch?

“…Later, as its sequenced genome became available, it was obvious that it would be very useful to study human diseases, as it is estimated that 42% of human genes that cause diseases have an orthologue in C. elegans [ 110 ]. Many worm models of polyQ disorders recapitulate phenotypes observed in diseases such as HD and some spinocerebellar ataxias (SCAs), among other disorders (reviewed by Rudich and Lamitina [ 111 ]). The readouts in polyQ models when assaying drugs or genetic modifiers depend on which tissue the polyQs are expressed on.…”

“…For example, worms that express polyQs fused to fluorescent proteins in muscle cells allow for investigation of the dynamics of polyQ aggregation and motor function. In contrast, when polyQs are expressed in neurons, complex behaviour such as mechanosensation or chemosensation can be studied [ 111 ]. Following this logic, many compounds have been assayed in different worm models of HD that express a track of polyQ in muscle cells (AM141) and ASH sensory neurons (HA759).…”