RNA-mediated neurodegeneration in repeat expansion disorders

Abstract

Most neurodegenerative disorders are thought to result primarily from the accumulation of misfolded proteins, which interfere with protein homeostasis in neurons. For a subset of diseases, however, noncoding regions of RNAs assume a primary toxic gain-of-function, leading to degeneration in many tissues, including the nervous system. Here we review a series of proposed mechanisms by which noncoding repeat expansions give rise to nervous system degeneration and dysfunction. These mechanisms include transcriptional alterations and the generation of antisense transcripts, sequestration of mRNA-associated protein complexes that lead to aberrant mRNA splicing and processing, and alterations in cellular processes, including activation of abnormal signaling cascades and failure of protein quality control pathways. We place these potential mechanisms in the context of known RNA-mediated disorders, including the myotonic dystrophies and fragile X tremor ataxia syndrome, and discuss recent results suggesting that mRNA toxicity may also play a role in some presumably protein-mediated neurodegenerative disorders. Lastly, we comment on recent progress in therapeutic development for these RNA-dominant diseases.

Figure 1. The sequestration hypothesis of RNA dominant disorders

Non-coding nucleotide repeat expansions can elicit cellular dysfunction in many tissues including the nervous system. A) Under normal conditions, numerous RNA binding proteins are involved in RNA splicing and processing, as well as in other cellular functions. B) Expanded nucleotide repeat sequences in RNA induce secondary hairpin structures that bind to and sequester numerous RNA binding proteins, including splicing factors (red circles), as well as factors involved in transcription and RNA trafficking (represented by green triangles). The sequestration of these factors by the toxic RNA prevents the normal splicing and processing of other mRNAs, leading to retention of rare (often fetal) splice isoforms. These isoforms are either less stable and thus rapidly degraded, or they encode proteins with different functional characteristics from the major isoforms usually produced. In the central nervous system, splicing errors can also interfere with proper distribution of the mRNA within neurons, especially dendrites.

Figure 2. Transcriptional Dysregulation and Antisense Transcripts in repeat expansion diseases

In addition to effects on RNA splicing, expanded non-coding nucleotide repeats likely lead to neurodegeneration via a number of overlapping mechanisms. A) At the level of DNA, the repeats themselves may impact both the temporal expression (as in congenital Myotonic Dystrophy) and the level of expression of the expanded repeat containing mRNAs (as in Fragile X Tremor Ataxia Syndrome, FXTAS) by altering local chromatin structure. B) In many cases, anti-sense transcripts through the repeat sequence are also produced. These antisense transcripts may be translated into poly-amino acid containing proteins (e.g. polyglutamine proteins in SCA 8), elicit toxicity directly at the RNA level, or both. They also may play a role in regulating the stability of the expanded repeat containing sense transcripts.

Figure 3. Therapeutic Development in RNA mediated Diseases

Recent studies support at least two therapeutic approaches to RNA dominant diseases. A) Eliminating the toxic RNA hairpin structure can be achieved using short antisense oligonucleotide transcripts. Depending on how they are constructed, the oligonucleotides can either lead to the degradation of the toxic RNA or interfere with the formation of the hairpin structure that is thought to elicit toxicity. B) Small molecules can be used to interfere directly with the interaction between toxic RNA and its binding proteins. Both treatments free the sequestered RNA binding proteins to perform their normal functions, thus restoring RNA processing homeostasis.