Repeat RNA expansion disorders of the nervous system: post-transcriptional mechanisms and therapeutic strategies

Abstract

Dozens of incurable neurological disorders result from expansion of short repeat sequences in both coding and non-coding regions of the transcriptome. Short repeat expansions underlie microsatellite repeat expansion (MRE) disorders including myotonic dystrophy (DM1, CUG 50–3,500 in DMPK ; DM2, CCTG 75–11,000 in ZNF9), fragile X tremor ataxia syndrome (FXTAS, CGG 50–200 in FMR1), spinal bulbar muscular atrophy (SBMA, CAG 40–55 in AR), Huntington’s disease (HD, CAG 36–121 in HTT), C9ORF72-amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD and C9-ALS/FTD, GGGGCC in C9ORF72), and many others, like ataxias. Recent research has highlighted several mechanisms that may contribute to pathology in this heterogeneous class of neurological MRE disorders – bidirectional transcription, intranuclear RNA foci, and repeat associated non-AUG (RAN) translation – which are the subject of this review. Additionally, many MRE disorders share similar underlying molecular pathologies that have been recently targeted in experimental and preclinical contexts. We discuss the therapeutic potential of versatile therapeutic strategies that may selectively target disrupted RNA-based processes and may be readily adaptable for the treatment of multiple MRE disorders. Collectively, the strategies under consideration for treatment of multiple MRE disorders include reducing levels of toxic RNA, preventing RNA foci formation, and eliminating the downstream cellular toxicity associated with peptide repeats produced by RAN translation. While treatments are still lacking for the majority of MRE disorders, several promising therapeutic strategies have emerged and will be evaluated within this review.

Recent Advances in RNA Therapy and Its Carriers to Treat the Single-Gene Neurological Disorders

“…As aforementioned, microsatellite repeat expansion (MRE) in both coding and non-coding regions of the genome has been associated with many neurological disorders, such as Huntington’s disease (HD), spinocerebellar ataxia, Friedreich ataxia, myotonic dystrophy, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) [ 161 ]. The hallmark for these MRE-associated disorders is the disturbances in the RNA metabolism resulting from the expansion of the repeat sequence which affects the proper translation and protein degradation [ 162 ].…”

Glial dysregulation in human brain in Fragile X-related disorders

“…Large trinucleotide (CGG) expansion (i.e., full mutations, FM) in the 5’ UTR of the FMR1 gene are associated with the neurodevelopmental disorder Fragile X Syndrome (FXS) while smaller, premutations (PM) are associated with Fragile X-associated tremor and ataxia syndrome (FXTAS), a late onset condition characterized by executive functioning decline and progressive cerebellar ataxia, presenting in 40-70% of PM carriers (Fu et al, 1991; Pieretti et al, 1991; Verkerk et al, 1991; Jacquemont et al, 2003; Grigsby et al, 2016). In the latter, neuropathological and imaging studies have identified intranuclear neuronal and astrocytic inclusions, prominent white matter abnormalities including myelin pallor and spongiosis, and characteristic T2 white matter hyperintensities on MRI (Jacquemont et al, 2003; Tassone et al, 2004; Cohen et al, 2006; Greco et al, 2006; Schwartz et al, 2021). In contrast, in Fragile X syndrome, an early-onset neurodevelopmental disorder characterized by intellectual disability, autistic symptoms and characteristic facial features (Martin & Bell, 1943; Turner et al, 1975), only subtle functional changes in white matter in humans have been identified on imaging (Hallahan et al, 2011; Sandoval et al, 2018; Swanson et al, 2018).…”

“…Prior studies in post-mortem human brain in both FXS and FXTAS have focused on bulk cellular analysis, which does not resolve cell-type specific molecular alterations. Whereas it is possible that the cellular heterogeneity of the human CNS may mask toxic levels of FMR1 mRNA, other hypotheses, including an inappropriate DNA damage response, mitochondrial stress, and polyglycine-containing peptide accumulation, have been put forth as alternative hypotheses to explain the pathophysiology of FXTAS (Garcia-Arocena & Hagerman, 2010;Sellier et al, 2017;Schwartz et al, 2021). It is also possible that reduced FMRP contributes to PM pathology in a developmentally distinct manner from the total loss that occurs in FXS.…”

Neurodegenerative Diseases and Cholesterol: Seeing the Field Through the Players

“…Neurodegenerative disorders devastate millions of lives worldwide and impose an increasing socio-economic burden (Kalia and Lang, 2015 ; Feigin et al, 2017 ; Erkkinen et al, 2018 ; El-Hayek et al, 2019 ). Research within the last decades has helped to clarify the mechanisms underlying each disease and suggested new therapeutic approaches (Fu et al, 2018 ; Ga et al, 2018 ; Jucker and Walker, 2018 ; Reich et al, 2018 ; Lassmann, 2019 ; Savelieff et al, 2019 ; Schwartz et al, 2021 ). A decisive step is the identification of molecular culprits that provoke or contribute to the dysfunction and degeneration of neurons.…”

“…Huntingtin has been at the center of attention as the long-sought gene bearing Huntington’s disease (HD)-causing mutations (The Huntington’s Disease Collaborative Research Group, 1993 ). Repeat expansions similar to those induced by the Huntingtin alleles cause neurodegeneration in numerous diseases including ALS and frontotemporal dementia by combinations of distinct molecular mechanisms (Malik et al, 2021 ; Schwartz et al, 2021 ). Research on multiple sclerosis (MS) has focused on immune and glial cells since chronic inflammation and demyelination are known pathologic changes preceding neurodegeneration (Faissner et al, 2019 ; Lassmann, 2019 ; Voet et al, 2019 ).…”