Dysregulated axonal RNA translation in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease that has been associated with a diverse array of genetic changes. Prominent among these are mutations in RNA-binding proteins (RBPs) or repeat expansions that give rise to toxic RNA species. RBPs are additionally central components of pathologic aggregates that constitute a disease hallmark, suggesting that dysregulation of RNA metabolism underlies disease progression. In the context of neuronal physiology, transport of RNAs and localized RNA translation in axons are fundamental to neuronal survival and function. Several lines of evidence suggest that axonal RNA translation is a central process perturbed by various pathogenic events associated with ALS. Dysregulated translation of specific RNA groups could underlie feedback effects that connect and reinforce disease manifestations. Among such candidates are RNAs encoding proteins involved in the regulation of microtubule dynamics. Further understanding of axonally dysregulated RNA targets and of the feedback mechanisms they induce could provide useful therapeutic insights. WIREs RNA 2016, 7:589-603. doi: 10.1002/wrna.1352 For further resources related to this article, please visit the WIREs website.

Figure 1

Axonal RNA translation as a central process dysregulated in amyotrophic lateral sclerosis (ALS). Potential interconnections between ALS‐associated pathogenic events and feedback effects discussed in the text. Disparate genetic mutations or environmental triggers could provide different points of entry to initiate cascades of events leading to dysregulation of RNA metabolism in axons through affecting RNA transport and/or translation. Red fonts indicate affected RNAs or events that could impact on axonal RNA translation.

Figure 2

RNA‐binding protein (RBP) aggregation and connections to microtubule dynamics. RBP aggregates associated with amyotrophic lateral sclerosis (ALS) can lead to translation arrest, ectopic translation, or sequestration of RBPs and subsequent perturbation in axonal RNA transport. Some of the affected RNAs encode microtubule regulators thus leading to alterations in microtubule dynamics. Such RNAs include the futsch/MAP1B RNA affected by TDP‐43 mutations or APC‐associated RNAs that can be affected by APC sequestration in FUS granules. Changes of the microtubule cytoskeleton could subsequently affect transport of additional cargo, such as mitochondria, or could have feedback effects on the dynamics of RNA granules.