Disruption of RNA Metabolism in Neurological Diseases and Emerging Therapeutic Interventions

Abstract

RNA binding proteins are critical to the maintenance of the transcriptome via controlled regulation of RNA processing and transport. Alterations of these proteins impact multiple steps of the RNA life cycle resulting in various molecular phenotypes such as aberrant RNA splicing, transport, and stability. Disruption of RNA binding proteins and widespread RNA processing defects are increasingly recognized as critical determinants of neurological diseases. Here, we describe distinct mechanisms by which the homeostasis of RNA binding proteins is compromised in neurological disorders through their reduced expression level, increased propensity to aggregate or sequestration by abnormal RNAs. These mechanisms all converge toward altered neuronal function highlighting the susceptibility of neurons to deleterious changes in RNA expression and the central role of RNA binding proteins in preserving neuronal integrity. Emerging therapeutic approaches to mitigate or reverse alterations of RNA binding proteins in neurological diseases are discussed.

Inclusion bodies formed by polyglutamine and poly(glycine-alanine) are enriched with distinct proteomes but converge in proteins that are risk factors for disease and involved in protein degradation

“…Overall both inclusions yielded an enrichment for gene ontology and KEGG networks of microtubule cytoskeleton, proteasome complex, chaperones, RNA splicing and nuclear envelope (Fig 2C; Table S3). These findings are in accordance with prior findings that protein aggregation impacts these biological processes and in particular an involvement in machinery for their clearance and degradation [49-52].…”

Survival Motor Neuron Protein Participates in Mouse Germ Cell Development and Spermatogonium Maintenance

“…At the molecule level, our data indicate that the deficiency of SMN in germ cells results in elevated levels of unresolved RNA:DNA hybrids, the so-called R-loop, a structure that forms over transcription pause sites, contributes to genome instability, and induces repressive marks on chromatin [25,36]. SMN is the key player, which interacts with the RNA helicase SETX, affects transcription termination, and regulates polymerase II activity by resolving the R-loop structure [10,37]. Unresolved RNA:DNA hybrids, induced by SMN depletion, lead to transcriptional termination and consequently cell cycle arrest (Figure 4) [10,11].…”

Platelet miRNA bio-signature discriminates between dementia with Lewy bodies and Alzheimer disease

“…Putative target genes were related to cell senescence, inflammation and signalling, and to RNA metabolism, especially to mitochondrial tRNA and gene silencing by small RNA. The disruption of RNA metabolism alterations in RNA splicing and processing, together with the deregulation of non-coding RNA has been described in several brain disorders (Nussbacher et al, 2019). In early PD brains, alterations in the small RNA profile are specifically related to tRNA fragments (Pantano et al, 2015).…”