Repeat expansion disease: progress and puzzles in disease pathogenesis

Abstract

Repeat expansion mutations cause at least 22 inherited neurological diseases. The complexity of repeat disease genetics and pathobiology has revealed unexpected shared themes and mechanistic pathways among the diseases, such as RNA toxicity. Also, investigation of the polyglutamine diseases has identified post-translational modification as a key step in the pathogenic cascade and has shown that the autophagy pathway has an important role in the degradation of misfolded proteins--two themes that are likely to be relevant to the entire neurodegeneration field. Insights from repeat disease research are catalysing new lines of study that should not only elucidate molecular mechanisms of disease but also highlight opportunities for therapeutic intervention for these currently untreatable disorders.

Figure 1. RNA toxicity in repeat expansion disease

An important mechanism that is now well-established for many repeat expansion diseases is the toxicity of RNAs containing expanded repeat sequences. In these diseases, the toxic RNAs interact with different RNA binding proteins (coloured shaped) to produce disease. This is a “trans-dominant” model of RNA toxicity: interaction of mutant RNA with RNA binding proteins is envisioned to interfere with the functions of the interacting proteins, which leads to abnormalities in the pathways regulated by the RNA binding proteins.

Figure 2. Sense and antisense toxicity

For a subset of repeat expansion diseases, sense and anti-sense transcripts are produced from the the repeat region. In these cases, one transcript may cause toxicity through a RNA gain-of-function pathway and the other transcript, which is generated in opposite orientation, may yield a toxic poly amino-acid tract containing protein. In the example shown here for SCA8, a transcript containing a CUG repeat expansion is hypothesized to produce toxicity, and a polyglutamine protein encoded from an anti-sense transcript is predicted to simultaneously produce toxicity. Even for diseases that do not exhibit bidirectional overlapping transcription, such as SCA3, concomitant RNA toxicity from the RNA transcript containing the CAG repeat expansion has been proposed. Hence, one must now consider the potential toxic contribution of different gene products (RNA and protein) from the sense strand - as well as the potential toxic contribution of different gene products from anti-sense overlapping transcription.