scholarly journals Widespread Alterations in Translation Elongation in the Brain of Juvenile Fmr1 Knock-Out Mice

2018 ◽  
Author(s):  
Sohani Das Sharma ◽  
Jordan B. Metz ◽  
Hongyu Li ◽  
Benjamin D. Hobson ◽  
Nicholas Hornstein ◽  
...  

SummaryFMRP is a polysome-associated RNA-binding protein encoded by Fmr1 that is lost in Fragile X syndrome. Increasing evidence suggests that FMRP regulates both translation initiation and elongation, but the gene-specificity of these effects is unclear. To elucidate the impact of Fmr1 loss on translation, we used ribosome profiling for genome-wide measurements of ribosomal occupancy and positioning in the cortex of 24 day-old Fmr1 knock-out mice. We found a remarkably coherent reduction in ribosome footprint abundance per mRNA for previously identified, high-affinity mRNA binding partners of FMRP, and an increase for terminal oligo-pyrimidine (TOP) motif-containing genes canonically controlled by mTOR-4EBP-eIF4E signaling. Amino acid motif- and gene-level analyses both showed a widespread reduction of translational pausing in Fmr1 knock-out mice. Our findings are consistent with a model of FMRP-mediated regulation of both translation initiation through eIF4E and elongation that is disrupted in Fragile X syndrome.




2020 ◽  
Author(s):  
Sameer Aryal ◽  
Francesco Longo ◽  
Eric Klann

AbstractLoss of the fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS). FMRP is widely thought to repress protein synthesis, but its translational targets and modes of control remain in dispute. We previously showed that genetic removal of p70 S6 kinase 1 (S6K1) corrects altered protein synthesis as well as synaptic and behavioral phenotypes in FXS mice. In this study, we examined the gene-specificity of altered mRNA translation in FXS and the mechanism of rescue with genetic reduction of S6K1 by carrying out ribosome profiling and RNA-Seq on cortical lysates from wild-type, FXS, S6K1 knockout, and double knockout mice. We observed reduced ribosome footprint abundance in the majority of differentially translated genes in the cortices of FXS mice. We used molecular assays to discover evidence that the reduction in ribosome footprint abundance reflects an increased rate of ribosome translocation, which is captured as a decrease in the number of translating ribosomes at steady state, and is normalized by inhibition of S6K1. We also found that genetic removal of S6K1 prevented a positive-to-negative gradation of alterations in translation efficiencies (RF/mRNA) with coding sequence length across mRNAs in FXS mouse cortices. Our findings reveal the identities of dysregulated mRNAs and a molecular mechanism by which reduction of S6K1 prevents altered translation in FXS.



2020 ◽  
Author(s):  
Chu-Hui Lin ◽  
Ting Zeng ◽  
Jian-Hong Lin ◽  
Feng Xiao ◽  
Bing-Mei Li ◽  
...  

Abstract Background: Fragile X syndrome (FXS), tightly related to the morbidity of Autism spectrum disorder (ASD), is a common hereditary syndrome often associated with retardation of intelligence. Some key symptoms of ASD such as anxiety, cognitive impairment and social anxiety disorder are also the predominant features in FXS. Children with ASD are often performed with gastrointestinal symptoms. According to the existing research, with the treatment with Bacteroides Fragilis BF839, mice with ASD will have better performance in communication and social behaviours with less anxiety and perceptual disorder. In this article, we have observed the impact of Bacteroides Fragilis BF839, a well-established Chinese bacteria strain with the human intestine origin, on mice with FXS and their behavioural disorders accordingly. Result: Based on the Open Field test, compared to the Fmr1KO group, mice treated with BF839 showed prolonged staying time in the center of the container. This finding suggests that BF839 can improve Fmr1KO mice's self-exploration behaviour and dented their anxiety. The Elevated Plus Maze test indicated BF839 treated mice presented more activities in entering open arms, prolonged time of staying and significantly less distance travelled at the plus-maze, along with less entering behaviours in the closed arms with less time of staying and more distance travelled. This result proved that with the treatment of BF839, Fmr1KO mice have improved ability in recognizing the surrounding environment and greater senses at detecting danger. Three-box Social Interaction test confirmed that BF839 strengthens the social novelty preference of the Fmr1KO mice, proven by their increasing duration and frequency in social interacting with the stranger mouse. The final experiment named the Pool Maze test presented the result that on the fourth day, BF839 treated mice have shown significantly shortened escape latency. Meanwhile, on Day 5, BF839 treated group performed increasing frequency in passing through the platform, which, along with the shortened escape latency, demonstrated BF839 has the function of improving Fmr1KO mice's cognitive capacity and their ability to extract information from the surrounding environment.Conclusion: Based on the outcome of each test performed, Bacteroides Fragilis BF839 can successfully improve Autism related abnormal behaviours in mice with FXS. Bacteroides Fragilis BF839 can be a potential intervention strategy in treating FXS and ASD safely and effectively.



2020 ◽  
Vol 48 (17) ◽  
pp. 9478-9490
Author(s):  
Juraj Szavits-Nossan ◽  
Luca Ciandrini

Abstract One of the main goals of ribosome profiling is to quantify the rate of protein synthesis at the level of translation. Here, we develop a method for inferring translation elongation kinetics from ribosome profiling data using recent advances in mathematical modelling of mRNA translation. Our method distinguishes between the elongation rate intrinsic to the ribosome’s stepping cycle and the actual elongation rate that takes into account ribosome interference. This distinction allows us to quantify the extent of ribosomal collisions along the transcript and identify individual codons where ribosomal collisions are likely. When examining ribosome profiling in yeast, we observe that translation initiation and elongation are close to their optima and traffic is minimized at the beginning of the transcript to favour ribosome recruitment. However, we find many individual sites of congestion along the mRNAs where the probability of ribosome interference can reach $50\%$. Our work provides new measures of translation initiation and elongation efficiencies, emphasizing the importance of rating these two stages of translation separately.





2020 ◽  
Vol 10 (4) ◽  
pp. 239
Author(s):  
Debra L. Reisinger ◽  
Rebecca C. Shaffer ◽  
Nicole Tartaglia ◽  
Elizabeth Berry-Kravis ◽  
Craig A. Erickson

Restricted repetitive behaviors (RRBs) are a core area of impairment in autism spectrum disorder (ASD), but also affect several other neurodevelopmental disorders including fragile X syndrome (FXS). Current literature has begun to describe the RRB profile in FXS up through adolescence; however, little is known about the subtypes of RRBs in adolescents and adults. Further, literature on the RRB profile of females with FXS is limited. The present study examines the RRB profile across subtypes and specific items in both males and females with FXS while assessing for differences based on age, ASD diagnosis and the impact of IQ. Participants included 154 individuals with FXS (ages 2 to 50 years old). Results revealed a peak in RRB severity in FXS between 7–12 years for the majority of RRB subscales with the exception of Sensory-Motor behaviors peaking between 2 and 12 years before declining. Distinct RRB profiles in males and females with FXS emerged in addition to significant overlap among the item and subscale levels of RRBs across gender. Further, an added diagnosis of ASD significantly increased rates of RRBs across all subscale levels, but not necessarily across all items. Lastly, IQ did not solely account for the presence of RRBs in FXS, with Sensory-Motor behaviors being driven by comorbid ASD in males with FXS, and Restricted Interest behaviors being driven by comorbid ASD regardless of gender. These findings build on the current understanding of RRBs in FXS based on gender and comorbid ASD and lay important groundwork for the development of targeted behavioral and pharmacological treatments.



2020 ◽  
Vol 34 (S1) ◽  
pp. 1-1
Author(s):  
Jessica L. Armstrong ◽  
Yiming Chen ◽  
Tanishka S. Saraf ◽  
Clinton E. Canal


eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Raeann Goering ◽  
Laura I Hudish ◽  
Bryan B Guzman ◽  
Nisha Raj ◽  
Gary J Bassell ◽  
...  

The sorting of RNA molecules to subcellular locations facilitates the activity of spatially restricted processes. We have analyzed subcellular transcriptomes of FMRP-null mouse neuronal cells to identify transcripts that depend on FMRP for efficient transport to neurites. We found that these transcripts contain an enrichment of G-quadruplex sequences in their 3′ UTRs, suggesting that FMRP recognizes them to promote RNA localization. We observed similar results in neurons derived from Fragile X Syndrome patients. We identified the RGG domain of FMRP as important for binding G-quadruplexes and the transport of G-quadruplex-containing transcripts. Finally, we found that the translation and localization targets of FMRP were distinct and that an FMRP mutant that is unable to bind ribosomes still promoted localization of G-quadruplex-containing messages. This suggests that these two regulatory modes of FMRP may be functionally separated. These results provide a framework for the elucidation of similar mechanisms governed by other RNA-binding proteins.



2018 ◽  
Vol 47 (5) ◽  
pp. e25-e25 ◽  
Author(s):  
Botao Liu ◽  
Gemma Molinaro ◽  
Huan Shu ◽  
Emily E Stackpole ◽  
Kimberly M Huber ◽  
...  


2019 ◽  
Vol 15 (4) ◽  
pp. 251-258 ◽  
Author(s):  
Dragana Protic ◽  
Maria J. Salcedo-Arellano ◽  
Jeanne Barbara Dy ◽  
Laura A. Potter ◽  
Randi J. Hagerman

Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability with prevalence rates estimated to be 1:5,000 in males and 1:8,000 in females. The increase of >200 Cytosine Guanine Guanine (CGG) repeats in the 5’ untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene results in transcriptional silencing on the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP), an RNA binding protein involved in the maturation and elimination of synapses. In addition to intellectual disability, common features of FXS are behavioral problems, autism, language deficits and atypical physical features. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Here we discuss several treatments that target the neurobiological pathway abnormal in FXS. These medications are clinically available at present and the data suggest that these medications can be helpful for those with FXS.



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