Partners in crime: Proteins implicated in RNA repeat expansion diseases

Abstract

Short tandem repeats are repetitive nucleotide sequences robustly distributed in the human genome. Their expansion underlies the pathogenesis of multiple neurological disorders, including Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, fragile X-associated tremor/ ataxia syndrome, and myotonic dystrophies, known as repeat expansion disorders (REDs). Several molecular pathomechanisms associated with toxic RNA containing expanded repeats (RNA exp ) are shared among REDs and contribute to disease progression, however, detailed mechanistic insight into those processes is limited. To deepen our understanding of the interplay between toxic RNA exp molecules and multiple protein partners, in this review, we discuss the roles of selected RNA-binding proteins (RBPs) that interact with RNA exp and thus act as "partners in crime" in the progression of REDs. We gather current findings concerning RBPs involved at different stages of the RNA exp life cycle, such as transcription, splicing, transport, and AUG-independent translation of expanded repeats. We argue that the activity of selected RBPs can be unique or common among REDs depending on the expanded repeat type. We also present proteins that are functionally depleted due to sequestration on RNA exp within nuclear foci and those which participate in RNA exp -dependent innate immunity activation.Abbreviations: 3 0 UTR/5 0 UTR, 3 0 /5 0 untranslated regions; AS, alternative splicing; ASO, antisense oligonucleotide; C9-ALS/FTD, C9orf72-linked amyotrophic lateral sclerosis and frontotemporal dementia; CAG exp , expanded CAG repeats; CCUG exp , expanded CCUG repeats; CGG exp , expanded CGG repeats; CTG exp , expanded CTG repeats; CUG exp , expanded CUG repeats;

RNA structure promotes liquid-to-solid phase transition of short RNAs in neuronal dysfunction

“…Our results demonstrate that the structure-specific properties of short RNAs can induce their liquid-to-solid phase transition in vitro, which can even be observed in vivo. These RNA foci induce the colocalization of RNA binding proteins and suppress the clonogenicity of cells, eventually induce cell death 11 , 12 .…”

Insufficiency of 40S ribosomal proteins, RPS26 and RPS25, negatively affects biosynthesis of polyglycine-containing proteins in fragile-X associated conditions

“…Currently, some RAN translation modifiers of FMR1 mRNA have been described. For instance, RNA helicases such as DDX3X (Linsalata et al , 2019) or DHX36 (Tseng et al , 2021), and others extensively reviewed in Baud et al (Baud et al , 2022)) have been identified as affecting CGG repeats-related RAN translation by facilitating ribosomal scanning via unwinding the structured RNA. Components of the endoplasmic reticulum ER-resident kinase (PERK) signaling pathway were shown to modulate RAN translation under stress conditions (Green et al , 2017), and the activity of another kinase, SRPK1, retains mutated FMR1 mRNA containing CGGexp in the nucleus blocking its transport to the cytoplasm and subsequent translation (Malik et al , 2021a).…”

“…Recently, different proteins involved in RAN translation regulation reviewed in Baud et al , 2022 were uncovered. However, mechanistic insight into this process remains unresolved.…”

Regulation potential of transcribed simple repeated sequences in developing neurons

“…Many SRSs are genetically unstable and frequently increase or decrease the number of repeated units as a result of replication or/and recombination errors. The genetic expansion of microsatellites in transcribed genomic regions is known to give rise to toxic RNAs in several neuromuscular and neurodegenerative disorders (Baud et al 2022; Ciesiolka et al 2017; Fujino and Nagai 2022; Schwartz et al 2021). For example, the type 1 myotonic dystrophy (DM1) is caused by the expansion of the CTG trinucleotide repeat in the 3’ untranslated region (3’UTR) of DMPK gene (Meola and Cardani 2015; Sznajder and Swanson 2019; Yum et al 2017).…”