Implications of mRNA translation dysregulation for neurological disorders

Jishi, Aya; Qi, Xin; Miranda, Helen Cristina

doi:10.1016/j.semcdb.2020.09.005

Cited by 21 publications

(11 citation statements)

References 77 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Emerging evidence revealed that neurons have a slower protein turnover than the rest of the cells, leading to extended protein half‐lives in the brain (about 3 times longer than rest of the tissues). As a consequence, alterations in mRNA translation will have specific long‐lasting effects in neurons (Jishi et al, 2021). Translation of synaptic proteins in neurons occurs continuously in both neuronal dendrites and in the synapse with dendritic‐localized mRNA, with nascent proteins then transported to synaptic sites (Hafner et al, 2019; Jung et al, 2012).…”

Section: Dysfunctions In Rna Metabolism and Leukodystrophiesmentioning

confidence: 99%

Role of epigenetics and alterations in RNA metabolism in leukodystrophies

Rey,

Esposito,

Maghraby

et al. 2024

WIREs RNA

View full text Add to dashboard Cite

Leukodystrophies are a class of rare heterogeneous disorders which affect the white matter of the brain, ultimately leading to a disruption in brain development and a damaging effect on cognitive, motor and social‐communicative development. These disorders present a great clinical heterogeneity, along with a phenotypic overlap and this could be partially due to contributions from environmental stimuli. It is in this context that there is a great need to investigate what other factors may contribute to both disease insurgence and phenotypical heterogeneity, and novel evidence are raising the attention toward the study of epigenetics and transcription mechanisms that can influence the disease phenotype beyond genetics. Modulation in the epigenetics machinery including histone modifications, DNA methylation and non‐coding RNAs dysregulation, could be crucial players in the development of these disorders, and moreover an aberrant RNA maturation process has been linked to leukodystrophies. Here, we provide an overview of these mechanisms hoping to supply a closer step toward the analysis of leukodystrophies not only as genetically determined but also with an added level of complexity where epigenetic dysregulation is of key relevance.This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNA RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development

show abstract

Section: Dysfunctions In Rna Metabolism and Leukodystrophiesmentioning

confidence: 99%

Role of epigenetics and alterations in RNA metabolism in leukodystrophies

Rey,

Esposito,

Maghraby

et al. 2024

WIREs RNA

View full text Add to dashboard Cite

show abstract

“…The downregulation of ribosomal genes could affect translation efficiency leading to protein synthesis dysregulation and corresponding to presentation of NDDs [60][61][62] . Recent studies of NDDs like Fragile X Syndrome and Tuberous Sclerosis have shown sex-specific differences in ribosomal function or translation regulation that may contribute to the sex-specific phenotypes [63][64][65][66] . Further studies on translational regulation will provide insights into the sex-specific pathological mechanisms of NDD.…”

Section: Dissecting Cnvs To Study Nddsmentioning

confidence: 99%

Dissecting 16p11.2 hemi-deletion to study sex-specific striatal phenotypes of neurodevelopmental disorders

Kim

Vanrobaeys

Peterson

et al. 2023

Preprint

View full text Add to dashboard Cite

Neurodevelopmental disorders (NDDs) are polygenic in nature and copy number variants (CNVs) are ideal candidates to study the nature of this polygenic risk. The disruption of striatal circuits is considered a central mechanism in NDDs. The 16p11.2 hemi-deletion (16p11.2 del) is one of the most common CNVs associated with NDD, and 16p11.2 del/+ mice show sex-specific striatum-related behavioral phenotypes. However, the critical genes among the 27 genes in the 16p11.2 region that underlie these phenotypes remain unknown. Previously, we applied a novel strategy to identify candidate genes associated with the sex-specific phenotypes of 16p11.2 del/+ mice and identified 3 genes of particular importance within the deleted region: thousand and one amino acid protein kinase 2 (Taok2), seizure-related 6 homolog-like 2 (Sez6l2), and major vault protein (Mvp). Using the CRISPR/Cas9 technique, we generated 3 gene hemi-deletion (3g del/+) mice carrying null mutations inTaok2, Sez6l2, and Mvp. We assessed striatum-dependent phenotypes of these 3g del/+ mice in behavioral, molecular, and imaging studies. Hemi-deletion of Taok2, Sez6l2, and Mvp induces sex-specific behavioral alterations in striatum-dependent behavioral tasks, specifically male-specific hyperactivity and impaired motivation for reward seeking, resembling behavioral phenotypes of 16p11.2 del/+ mice. Moreover, RNAseq analysis revealed that 3g del/+ mice exhibit gene expression changes in the striatum similar to 16p11.2 del/+ mice, but only in males. Pathway analysis identified ribosomal dysfunction and translation dysregulation as molecular mechanisms underlying male-specific, striatum-dependent behavioral alterations. Together, the mutation of 3 genes within the 16p11.2 region phenocopies striatal sex-specific phenotypes of 16p11.2 del/+ mice, unlike single gene mutation studies. These results support the importance of a polygenic approach to study NDDs and our novel strategy to identify genes of interest using gene expression patterns in brain regions, such as the striatum, which are impacted in these disorders.

show abstract

“…Moreover, a SNP in the c-Myc 5′UTR has been found to cause the overexpression of c-Myc in multiple myeloma (Chappell et al, 2000 ; Shi et al, 2016 ), and SNPs in the cis-acting regulatory motifs in the transcript leaders of connexin 32 and VEGFA has been linked to the development of two severe neurodegenerative disorders, the Charcot Marie Tooth disease and the amyotrophic lateral sclerosis (Hudder and Werner, 2000 ; Lambrechts et al, 2003 ). The emerging link between altered translational control of protein expression and neurodevelopmental and neurodegenerative human disorders (Jishi et al, 2021 ) is not surprising since translational regulation is particularly adopted by neurons, that need a very tight, sophisticated control of protein synthesis. In fact, their morphology and function require a highly dynamic and local control of protein expression since synapses are continuously tuned according to their activity that occurs far away from the nucleus (Holt et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Complex CDKL5 translational regulation and its potential role in CDKL5 deficiency disorder

Ruggiero,

Fagioli,

de Pretis

et al. 2023

Front. Cell. Neurosci.

View full text Add to dashboard Cite

CDKL5 is a kinase with relevant functions in correct neuronal development and in the shaping of synapses. A decrease in its expression or activity leads to a severe neurodevelopmental condition known as CDKL5 deficiency disorder (CDD). CDD arises from CDKL5 mutations that lie in the coding region of the gene. However, the identification of a SNP in the CDKL5 5′UTR in a patient with symptoms consistent with CDD, together with the complexity of the CDKL5 transcript leader, points toward a relevant translational regulation of CDKL5 expression with important consequences in physiological processes as well as in the pathogenesis of CDD. We performed a bioinformatics and molecular analysis of the 5'UTR of CDKL5 to identify translational regulatory features. We propose an important role for structural cis-acting elements, with the involvement of the eukaryotic translational initiation factor eIF4B. By evaluating both cap-dependent and cap-independent translation initiation, we suggest the presence of an IRES supporting the translation of CDKL5 mRNA and propose a pathogenic effect of the C>T -189 SNP in decreasing the translation of the downstream protein.

show abstract

Implications of mRNA translation dysregulation for neurological disorders

Cited by 21 publications

References 77 publications

Role of epigenetics and alterations in RNA metabolism in leukodystrophies

Role of epigenetics and alterations in RNA metabolism in leukodystrophies

Dissecting 16p11.2 hemi-deletion to study sex-specific striatal phenotypes of neurodevelopmental disorders

Complex CDKL5 translational regulation and its potential role in CDKL5 deficiency disorder

Contact Info

Product

Resources

About