Suppression of MEHMO Syndrome Mutation in eIF2 by Small Molecule ISRIB

Young‐Baird, Sara K.; Lourenço, Maíra Bertolessi; Elder, Megan K.; Klann, Eric; Liebau, Stefan; Dever, Thomas E.

doi:10.1016/j.molcel.2019.11.008

Cited by 31 publications

(21 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Depletion of MAP7D2 is associated with defects in axonal development and neuronal migration [25]. Mutations in EIF2S3 have been linked to MEHMO syndrome development, an X-linked intellectual disability disorder [26]. Interestingly, three switch genes, XIST, ZFX, and KDM6A, have been associated with X chromosome inactivation, the process by which mammals compensate for the unequal number of sex chromosomes.…”

Section: Identification Of Switch Genes In Alsmentioning

confidence: 99%

Network Analysis Identifies Sex-Specific Gene Expression Changes in Blood of Amyotrophic Lateral Sclerosis Patients

Santiago¹,

Quinn

Potashkin

2021

IJMS

View full text Add to dashboard Cite

Understanding the molecular mechanisms underlying the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating neurodegenerative disease, is a major challenge. We used co-expression networks implemented by the SWitch Miner software to identify switch genes associated with drastic transcriptomic changes in the blood of ALS patients. Functional analyses revealed that switch genes were enriched in pathways related to the cell cycle, hepatitis C, and small cell lung cancer. Analysis of switch genes by sex revealed that switch genes from males were associated with metabolic pathways, including PI3K-AKT, sphingolipid, carbon metabolism, FOXO, and AMPK signaling. In contrast, female switch genes related to infectious diseases, inflammation, apoptosis, and atherosclerosis. Furthermore, eight switch genes showed sex-specific gene expression patterns. Collectively, we identified essential genes and pathways that may explain sex differences observed in ALS. Future studies investigating the potential role of these genes in driving disease disparities between males and females with ALS are warranted.

show abstract

Section: Identification Of Switch Genes In Alsmentioning

confidence: 99%

Network Analysis Identifies Sex-Specific Gene Expression Changes in Blood of Amyotrophic Lateral Sclerosis Patients

Santiago¹,

Quinn

Potashkin

2021

IJMS

View full text Add to dashboard Cite

show abstract

“…A total of 5 µg protein was run on a NuPage TM 4-12% Bis-Tris Protein Gel (Invitrogen) using MOPS buffer according to manufacturer instructions and subsequently transferred to a nitrocellulose membrane according to the NuPage TM manufacturer's protocol (Invitrogen). Detection of phospho and total eIF2ɑ was performed as previously described (Young-Baird et al, 2020).…”

Section: Western For Phospho-eif2ɑmentioning

confidence: 99%

An alternative UPF1 isoform drives conditional remodeling of nonsense-mediated mRNA decay

Fritz

Ranganathan

Wang

et al. 2021

Preprint

View full text Add to dashboard Cite

The nonsense-mediated mRNA decay (NMD) pathway monitors translation termination to degrade transcripts with premature stop codons and regulate thousands of human genes. Due to the major role of NMD in RNA quality control and gene expression regulation, it is important to understand how the pathway responds to changing cellular conditions. Here we show that an alternative mammalian-specific isoform of the core NMD factor UPF1, termed UPF1LL, enables condition-dependent remodeling of NMD specificity. UPF1LL associates more stably with potential NMD target mRNAs than the major UPF1SL isoform, expanding the scope of NMD to include many transcripts normally immune to the pathway. Unexpectedly, the enhanced persistence of UPF1LL on mRNAs supports induction of NMD in response to rare translation termination events. Thus, while canonical NMD is abolished by translational repression, UPF1LL activity is enhanced, providing a mechanism to rapidly rewire NMD specificity in response to cellular stress.

show abstract

“…Not surprisingly, mutations altering the function and/or expression levels of RBPs with functions in translational regulation can be at the core of different neurodevelopmental disorders and also elicit accompanying syndromes. For example, a mutation that affects the C-terminal domain of the eukaryotic translation initiation factor eIF2γ was identified as a possible cause of MEHMO syndrome (Young-Baird et al, 2020 ). This syndrome is characterized by intellectual disability (ID), epilepsy, hypogenitalism, microcephaly, and obesity.…”

Section: Malfunction Of Rna Binding Proteins and Associated Diseasesmentioning

confidence: 99%

“…This syndrome is characterized by intellectual disability (ID), epilepsy, hypogenitalism, microcephaly, and obesity. In patient-derived induced pluripotent stem cells, the eIF2γ mutation decreases global translation levels due to defective assembly of eIF2 complexes (Young-Baird et al, 2020 ), which under normal circumstances assist in the selection of the translation initiation site and the delivery of the initiation methionyl-tRNA (Hinnebusch, 2014 ).…”

Section: Malfunction Of Rna Binding Proteins and Associated Diseasesmentioning

confidence: 99%

The Fine Art of Writing a Message: RNA Metabolism in the Shaping and Remodeling of the Nervous System

Landínez-Macías

Urwyler

2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Neuronal morphogenesis, integration into circuits, and remodeling of synaptic connections occur in temporally and spatially defined steps. Accordingly, the expression of proteins and specific protein isoforms that contribute to these processes must be controlled quantitatively in time and space. A wide variety of post-transcriptional regulatory mechanisms, which act on pre-mRNA and mRNA molecules contribute to this control. They are thereby critically involved in physiological and pathophysiological nervous system development, function, and maintenance. Here, we review recent findings on how mRNA metabolism contributes to neuronal development, from neural stem cell maintenance to synapse specification, with a particular focus on axon growth, guidance, branching, and synapse formation. We emphasize the role of RNA-binding proteins, and highlight their emerging roles in the poorly understood molecular processes of RNA editing, alternative polyadenylation, and temporal control of splicing, while also discussing alternative splicing, RNA localization, and local translation. We illustrate with the example of the evolutionary conserved Musashi protein family how individual RNA-binding proteins are, on the one hand, acting in different processes of RNA metabolism, and, on the other hand, impacting multiple steps in neuronal development and circuit formation. Finally, we provide links to diseases that have been associated with the malfunction of RNA-binding proteins and disrupted post-transcriptional regulation.

show abstract

Suppression of MEHMO Syndrome Mutation in eIF2 by Small Molecule ISRIB

Cited by 31 publications

References 65 publications

Network Analysis Identifies Sex-Specific Gene Expression Changes in Blood of Amyotrophic Lateral Sclerosis Patients

Network Analysis Identifies Sex-Specific Gene Expression Changes in Blood of Amyotrophic Lateral Sclerosis Patients

An alternative UPF1 isoform drives conditional remodeling of nonsense-mediated mRNA decay

The Fine Art of Writing a Message: RNA Metabolism in the Shaping and Remodeling of the Nervous System

Contact Info

Product

Resources

About