Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders

Castelli, Lydia M.; Huang, Wan-Ping; Lin, Ya-Hui; Chang, Kai Ming; Hautbergue, Guillaume M.

doi:10.1042/bst20200690

Cited by 18 publications

(16 citation statements)

References 175 publications

(157 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, measurements of ovarian dysfunction (FSH levels) and pituitary-adrenal dysfunction (prolactin, cortisol and ACTH levels) were not correlated with scores in the FXTAS motor rating scale in PM women [91], suggesting that endocrine and motor alterations in PM carriers do not have a simple relationship. Finally, no association has been observed between CGG repeats in the normal range and reproductive parameters (including FSH and AMH levels) [126], but there are some indications regarding high levels of FSH in cases bearing intermediate CGG sizes (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(50)(51)(52)(53)(54) and fecundity problems and amenorrhea [115], an observation that deserves further confirmation.…”

Section: Endocrine Biomarkers In Premutation Carriersmentioning

confidence: 95%

“…In addition to RNA, a pathogenic role has been proposed for a cryptic polyglycine peptide, FMRpolyG, that is produced by a repeat associated non-AUG (RAN) translation process occurring at the 5 -expanded CGG region of FMR1 [42,43]. First discovered in the ATXN8 gene which is involved in the Spinocerebellar ataxia 8 (SCA8), the products of RAN translation have been detected in vivo for other genes containing repetitive nucleotides such as Huntington's disease (HD), myotronic dystrophy type 1 and 2 (DM1, DM2), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) [44]. In the FMR1 locus, RAN translation can generate three types of homopeptides depending on the translation initiation (FMRpolyR, FMRpolyG and FMRpolyA), being the most efficient produced and the most well characterized the FMRpolyG (reviewed in [35]).…”

Section: Production Of Fmrpolyg Peptidesmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

Valor

Morales

Hervás-Corpión

et al. 2021

IJMS

View full text Add to dashboard Cite

Abnormal trinucleotide expansions cause rare disorders that compromise quality of life and, in some cases, lifespan. In particular, the expansions of the CGG-repeats stretch at the 5’-UTR of the Fragile X Mental Retardation 1 (FMR1) gene have pleiotropic effects that lead to a variety of Fragile X-associated syndromes: the neurodevelopmental Fragile X syndrome (FXS) in children, the late-onset neurodegenerative disorder Fragile X-associated tremor-ataxia syndrome (FXTAS) that mainly affects adult men, the Fragile X-associated primary ovarian insufficiency (FXPOI) in adult women, and a variety of psychiatric and affective disorders that are under the term of Fragile X-associated neuropsychiatric disorders (FXAND). In this review, we will describe the pathological mechanisms of the adult “gain-of-function” syndromes that are mainly caused by the toxic actions of CGG RNA and FMRpolyG peptide. There have been intensive attempts to identify reliable peripheral biomarkers to assess disease progression and onset of specific pathological traits. Mitochondrial dysfunction, altered miRNA expression, endocrine system failure, and impairment of the GABAergic transmission are some of the affectations that are susceptible to be tracked using peripheral blood for monitoring of the motor, cognitive, psychiatric and reproductive impairment of the CGG-expansion carriers. We provided some illustrative examples from our own cohort. Understanding the association between molecular pathogenesis and biomarkers dynamics will improve effective prognosis and clinical management of CGG-expansion carriers.

show abstract

Section: Endocrine Biomarkers In Premutation Carriersmentioning

confidence: 95%

Section: Production Of Fmrpolyg Peptidesmentioning

confidence: 99%

Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

Valor

Morales

Hervás-Corpión

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…Several of these repeat expansions are bi-directionally transcribed including in Fragile X associated mental retardations, C9ORF72-ALS/FTD, HD, DM and several subtypes of spinocerebellar ataxia (SCA 2, 3, 8, 12, 31, 37). For recent reviews, we refer to ( Castelli et al, 2021 ; Depienne and Mandel 2021 ).…”

Section: Introductionmentioning

confidence: 99%

“…Microsatellite expansions are located in coding and non-coding regions of the affected genes, with pathogenesis attributed to interconnecting mechanisms involving both RNA/proteins loss and gain of functions. Production of neurotoxic polymeric repeat proteins/peptides which are generated from repeat-associated non-AUG (RAN) translation in all frames and from coding or non-coding regions of genes were also evidenced in multiple repeat expansion disorders (reviewed in ( Castelli et al, 2021 ; Depienne and Mandel 2021 )).…”

Section: Introductionmentioning

confidence: 99%

RNA Helicases in Microsatellite Repeat Expansion Disorders and Neurodegeneration

et al. 2022

Self Cite

View full text Add to dashboard Cite

Short repeated sequences of 3−6 nucleotides are causing a growing number of over 50 microsatellite expansion disorders, which mainly present with neurodegenerative features. Although considered rare diseases in relation to the relatively low number of cases, these primarily adult-onset conditions, often debilitating and fatal in absence of a cure, collectively pose a large burden on healthcare systems in an ageing world population. The pathological mechanisms driving disease onset are complex implicating several non-exclusive mechanisms of neuronal injury linked to RNA and protein toxic gain- and loss- of functions. Adding to the complexity of pathogenesis, microsatellite repeat expansions are polymorphic and found in coding as well as in non-coding regions of genes. They form secondary and tertiary structures involving G-quadruplexes and atypical helices in repeated GC-rich sequences. Unwinding of these structures by RNA helicases plays multiple roles in the expression of genes including repeat-associated non-AUG (RAN) translation of polymeric-repeat proteins with aggregating and cytotoxic properties. Here, we will briefly review the pathogenic mechanisms mediated by microsatellite repeat expansions prior to focus on the RNA helicases eIF4A, DDX3X and DHX36 which act as modifiers of RAN translation in C9ORF72-linked amyotrophic lateral sclerosis/frontotemporal dementia (C9ORF72-ALS/FTD) and Fragile X-associated tremor/ataxia syndrome (FXTAS). We will further review the RNA helicases DDX5/17, DHX9, Dicer and UPF1 which play additional roles in the dysregulation of RNA metabolism in repeat expansion disorders. In addition, we will contrast these with the roles of other RNA helicases such as DDX19/20, senataxin and others which have been associated with neurodegeneration independently of microsatellite repeat expansions. Finally, we will discuss the challenges and potential opportunities that are associated with the targeting of RNA helicases for the development of future therapeutic approaches.

show abstract

“…Proposed pathophysiological mechanisms for the C9ORF72 mutation include production of dipeptide repeat proteins (DPRs), formation of RNA foci, which are the accumulation of transcribed expanded nucleotide repeats within the nucleus, and haploinsufficiency of the C9ORF72 protein. Despite its location in a non-coding region and lack of start codon, the repeat expansion undergoes an unconventional form of translation known as repeat associated non-AUG (RAN) translation in both sense and antisense directions to produce five neurotoxic DPRs ( Castelli et al, 2021 ). In addition to the typical TDP-43 pathology, C9ORF72-ALS/FTD shows specific DPR pathology from sense and antisense repeat expansion-containing transcripts, comprised of star shaped TDP-43 negative, tau-negative, ubiquitin-positive and p62-positive inclusions throughout the cerebellar cortex, neocortex, and hippocampus.…”

Section: Introduction To Als and Als-associated Proteinopathiesmentioning

confidence: 99%

Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis

et al. 2021

Self Cite

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons. As with the majority of neurodegenerative diseases, the pathological hallmarks of ALS involve proteinopathies which lead to the formation of various polyubiquitylated protein aggregates in neurons and glia. ALS is a highly heterogeneous disease, with both familial and sporadic forms arising from the convergence of multiple disease mechanisms, many of which remain elusive. There has been considerable research effort invested into exploring these disease mechanisms and in recent years dysregulation of RNA metabolism and mitochondrial function have emerged as of crucial importance to the onset and development of ALS proteinopathies. Widespread alterations of the RNA metabolism and post-translational processing of proteins lead to the disruption of multiple biological pathways. Abnormal mitochondrial structure, impaired ATP production, dysregulation of energy metabolism and calcium homeostasis as well as apoptosis have been implicated in the neurodegenerative process. Dysfunctional mitochondria further accumulate in ALS motor neurons and reflect a wider failure of cellular quality control systems, including mitophagy and other autophagic processes. Here, we review the evidence for RNA and mitochondrial dysfunction as some of the earliest critical pathophysiological events leading to the development of ALS proteinopathies, explore their relative pathological contributions and their points of convergence with other key disease mechanisms. This review will focus primarily on mutations in genes causing four major types of ALS (C9ORF72, SOD1, TARDBP/TDP-43, and FUS) and in protein homeostasis genes (SQSTM1, OPTN, VCP, and UBQLN2) as well as sporadic forms of the disease. Finally, we will look to the future of ALS research and how an improved understanding of central mechanisms underpinning proteinopathies might inform research directions and have implications for the development of novel therapeutic approaches.

show abstract

Mechanisms of repeat-associated non-AUG translation in neurological microsatellite expansion disorders

Cited by 18 publications

References 175 publications

Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

Molecular Pathogenesis and Peripheral Monitoring of Adult Fragile X-Associated Syndromes

RNA Helicases in Microsatellite Repeat Expansion Disorders and Neurodegeneration

Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis

Contact Info

Product

Resources

About