RNA Degradation in Neurodegenerative Disease

Abstract

Ribonucleic acid (RNA) homeostasis is dynamically modulated in response to changing physiological conditions. Tight regulation of RNA abundance through both transcription and degradation determines the amount, timing, and location of protein translation. This balance is of particular importance in neurons, which are among the most metabolically active and morphologically complex cells in the body. As a result, any disruptions in RNA degradation can have dramatic consequences for neuronal health. In this chapter, we will first discuss mechanisms of RNA stabilization and decay. We will then explore how the disruption of these pathways can lead to neurodegenerative disease.

Keywords: Alternative splicing; Decay; Disease; Exosome; Neurodegeneration; RNA; Stress granule; Transport.

Figure 1.

Pathways responsible for RNA homeostasis. RNA stability is promoted by two key mechanisms (left). Following transcription, nascent RNA is stabilized by the addition of a 5’ cap and poly(A) tail, as well as the formation of secondary structures. Transcripts are also sequestered and stabilized in stress granules upon exposure to cellular stress. In contrast, RNA degradation pathways target faulty transcripts for removal (right). Transcripts that contain premature stop codons are targeted by nonsense-mediated decay. When translation fails to stop or start, the associated transcripts are degraded by nonstop decay and no-go decay, respectively. RNA decay mechanisms also regulate transcript abundance through several elements located within the 3’ UTR, including AU-rich elements, Staufen binding sites, miRNA recognition elements, and constitutive decay elements. Lastly, P-bodies sequester and destabilize RNA transcripts.

Figure 2.

Abnormal RNA stability in neurodegenerative disease. Here we compare how normal pathways (left column) are disrupted in disease (right column). RNA Sequestration: There is constant flux between pools of RNA transcripts that are actively being translated (the polysome), those sequestered in stress granules, and those associated with P-bodies. In disease states, increased stress granule formation or reduced stress granule dissociation disrupts the equilibrium, resulting in fewer transcripts undergoing translation. Repeat Expansions and RNA Foci: Transcripts containing repeat expansions form secondary structures such as hairpin loops and G-quadruplexes that are often stabilized in nuclear foci, which also sequester RNA-binding proteins (green circles). These transcripts also generate proteins via RAN translation that can disrupt membraneless organelles involved in RNA splicing and processing. RNA Transport and the Exosome: Mutations in THO, Gle1, and other components of the RNA export pathway result in nuclear RNA retention and degradation via the exosome complex. Mutations in exosome components can inhibit RNA turnover and further disrupt RNA homeostasis. Alternative Splicing: Mutations that disrupt splice sites, or dysfunction of splicing regulators such as TDP43, result in the inclusion of unannotated or “cryptic” exons (pink). These transcripts are often targeted for nonsense-mediated decay. Retrotransposons: These transposable elements insert themselves into the genome, often disrupting open reading frames or splice sites. The transcripts that are transcribed from these regions are often faulty, and are targeted for RNA decay.