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Nature Biotechnology Nov 2023RNA base editing refers to the rewriting of genetic information within an intact RNA molecule and serves various functions, such as evasion of the endogenous immune... (Review)
Review
RNA base editing refers to the rewriting of genetic information within an intact RNA molecule and serves various functions, such as evasion of the endogenous immune system and regulation of protein function. To achieve this, certain enzymes have been discovered in human cells that catalyze the conversion of one nucleobase into another. This natural process could be exploited to manipulate and recode any base in a target transcript. In contrast to DNA base editing, analogous changes introduced in RNA are not permanent or inheritable but rather allow reversible and doseable effects that appeal to various therapeutic applications. The current practice of RNA base editing involves the deamination of adenosines and cytidines, which are converted to inosines and uridines, respectively. In this Review, we summarize current site-directed RNA base-editing strategies and highlight recent achievements to improve editing efficiency, precision, codon-targeting scope and in vivo delivery into disease-relevant tissues. Besides engineered editing effectors, we focus on strategies to harness endogenous adenosine deaminases acting on RNA (ADAR) enzymes and discuss limitations and future perspectives to apply the tools in basic research and as a therapeutic modality. We expect the field to realize the first RNA base-editing drug soon, likely on a well-defined genetic disease. However, the long-term challenge will be to carve out the sweet spot of the technology where its unique ability is exploited to modulate signaling cues, metabolism or other clinically relevant processes in a safe and doseable manner.
Topics: Humans; RNA; Gene Editing
PubMed: 37735261
DOI: 10.1038/s41587-023-01927-0 -
Brain Stimulation 2023Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2), severely impairs learning and memory. We previously showed...
BACKGROUND
Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2), severely impairs learning and memory. We previously showed that forniceal deep brain stimulation (DBS) stimulates hippocampal neurogenesis with concomitant improvements in hippocampal-dependent learning and memory in a mouse model of RTT.
OBJECTIVES
To determine the duration of DBS benefits; characterize DBS effects on hippocampal neurogenesis; and determine whether DBS influences MECP2 genotype and survival of newborn dentate granular cells (DGCs) in RTT mice.
METHODS
Chronic DBS was delivered through an electrode implanted in the fimbria-fornix. We tested separate cohorts of mice in contextual and cued fear memory at different time points after DBS. We then examined neurogenesis, DGC apoptosis, and the expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) after DBS by immunohistochemistry.
RESULTS
After two weeks of forniceal DBS, memory improvements lasted between 6 and 9 weeks. Repeating DBS every 6 weeks was sufficient to maintain the improvement. Forniceal DBS stimulated the birth of more MeCP2-positive than MeCP2-negative DGCs and had no effect on DGC survival. It also increased the expression of BDNF but not VEGF in the RTT mouse dentate gyrus.
CONCLUSION
Improvements in learning and memory from forniceal DBS in RTT mice extends well beyond the treatment period and can be maintained by repeated DBS. Stimulation of BDNF expression correlates with improvements in hippocampal neurogenesis and memory benefits.
Topics: Mice; Animals; Rett Syndrome; Brain-Derived Neurotrophic Factor; Deep Brain Stimulation; Vascular Endothelial Growth Factor A; Hippocampus; Neurogenesis
PubMed: 37704033
DOI: 10.1016/j.brs.2023.09.002 -
Canadian Journal of Pain = Revue... 2023Although delayed or decreased responses to pain are commonly reported among caregivers of individuals with Rett syndrome (RTT), previous studies in relatively small...
BACKGROUND
Although delayed or decreased responses to pain are commonly reported among caregivers of individuals with Rett syndrome (RTT), previous studies in relatively small samples have documented that caregivers are concerned about pain, particularly due to gastrointestinal and musculoskeletal conditions.
AIMS
The purpose of the current study was to investigate in detail caregivers' perceptions of pain sensitivity, as well as the types, severity, and effect of pain experienced by individuals with RTT in a larger sample than previous studies.
METHODS
A total of 51 caregivers (mostly mothers) participated in the study, which involved standardized questionnaires and interviews. The individuals with RTT ranged in age from 2 to 52 years of age, and most ( = 46; 90%) met criteria for classic RTT.
RESULTS
Across the sample, 84% of caregivers reported that they believed that their child was less sensitive to pain compared to her typically developing peers. Despite this perception, 63% of caregivers reported that their child had experienced at least one form of pain in the previous 7 days, and 57% reported their child experienced at least one form of chronic pain. On average, caregivers reported that their child's pain was of moderate severity and interfered with at least one activity of daily living.
CONCLUSIONS
The results suggest that pain is a substantial concern among caregivers of individuals with RTT and indicate that additional research is needed to understand the apparent paradox of frequently reported pain experiences despite widespread perceptions of decreased pain sensitivity.
PubMed: 37533505
DOI: 10.1080/24740527.2023.2229400 -
Human Molecular Genetics Dec 2023Genes mutated in monogenic neurodevelopmental disorders are broadly expressed. This observation supports the concept that monogenic neurodevelopmental disorders are...
Genes mutated in monogenic neurodevelopmental disorders are broadly expressed. This observation supports the concept that monogenic neurodevelopmental disorders are systemic diseases that profoundly impact neurodevelopment. We tested the systemic disease model focusing on Rett syndrome, which is caused by mutations in MECP2. Transcriptomes and proteomes of organs and brain regions from Mecp2-null mice as well as diverse MECP2-null male and female human cells were assessed. Widespread changes in the steady-state transcriptome and proteome were identified in brain regions and organs of presymptomatic Mecp2-null male mice as well as mutant human cell lines. The extent of these transcriptome and proteome modifications was similar in cortex, liver, kidney, and skeletal muscle and more pronounced than in the hippocampus and striatum. In particular, Mecp2- and MECP2-sensitive proteomes were enriched in synaptic and metabolic annotated gene products, the latter encompassing lipid metabolism and mitochondrial pathways. MECP2 mutations altered pyruvate-dependent mitochondrial respiration while maintaining the capacity to use glutamine as a mitochondrial carbon source. We conclude that mutations in Mecp2/MECP2 perturb lipid and mitochondrial metabolism systemically limiting cellular flexibility to utilize mitochondrial fuels.
Topics: Animals; Female; Humans; Male; Mice; Brain; Disease Models, Animal; Methyl-CpG-Binding Protein 2; Mice, Inbred C57BL; Mice, Knockout; Phenotype; Proteome; Rett Syndrome
PubMed: 37712894
DOI: 10.1093/hmg/ddad154 -
Augmentative and Alternative... Dec 2023Due to loss of spoken language and resulting complex communication needs, people with Rett syndrome are obvious candidates for communication intervention. To advance... (Review)
Review
Due to loss of spoken language and resulting complex communication needs, people with Rett syndrome are obvious candidates for communication intervention. To advance evidence-based practice and guide future research efforts, we identified and summarized 16 communication intervention studies published since a previous 2009 review on this topic. Studies were summarized in terms of (a) participants, (b) dependent variables related to communication, (c) intervention characteristics, (d) outcomes, and (e) certainty of evidence. Across the 16 studies, intervention was provided to a total of 100 participants from 3 to 47 years of age. Half of the studies used systematic instruction to teach aided AAC. Other interventions and associated technologies included music therapy, eye tracking technology, and transcranial stimulation. Positive outcomes (e.g., using AAC devices to make requests and/or initiate social-communication interactions) were reported in 13 of the studies. These 16 new studies provide additional guidance on how to enhance the communicative functioning of people with Rett syndrome. Future research directions are highlighted.
Topics: Humans; Rett Syndrome; Communication Disorders; Communication Aids for Disabled; Communication; Narration
PubMed: 37526342
DOI: 10.1080/07434618.2023.2215864 -
The Journal of the Acoustical Society... Aug 2023Mice communicate through audible vocalizations, which are within the human hearing range, and ultrasonic vocalizations (USVs), which are above the upper limit of human... (Review)
Review
Mice communicate through audible vocalizations, which are within the human hearing range, and ultrasonic vocalizations (USVs), which are above the upper limit of human hearing. USVs are produced by rodents in social contexts including pup separation, territorial, and courting assays. Like birdsong, an established model for human speech, USVs in mice have been used as a model for understanding human communication. Their utility as a model of social communication is illustrated in neurodevelopmental conditions with a genetic basis, like autism spectrum disorders and Rett syndrome. As mice do not exhibit clear visual cues when they vocalize, the source of vocalization is often assumed. Therefore, there is potential to better discern the true vocal contribution of individual mice if the upper limit of human hearing were to be extended. Currently, there are efforts to increase the precision of sound-localizing technology, which will develop our understanding of communication in mice and other animal models.
Topics: Animals; Humans; Mice; Ultrasonics; Vocalization, Animal; Speech; Sound; Communication
PubMed: 37540096
DOI: 10.1121/10.0020544 -
Archives of Biochemistry and Biophysics Jul 2024To date, Rett syndrome (RTT), a genetic disorder mainly caused by mutations in the X-linked MECP2 gene, is increasingly considered a broad-spectrum pathology, instead of... (Review)
Review
To date, Rett syndrome (RTT), a genetic disorder mainly caused by mutations in the X-linked MECP2 gene, is increasingly considered a broad-spectrum pathology, instead of just a neurodevelopmental disease, due to the multitude of peripheral co-morbidities and the compromised metabolic pathways, affecting the patients. The altered molecular processes include an impaired mitochondrial function, a perturbed redox homeostasis, a chronic subclinical inflammation and an improper cholesterol metabolism. The persistent subclinical inflammatory condition was first defined ten years ago, as a previously unrecognized feature of RTT, playing a role in the pathology progress and modulation of phenotypical severity. In light of this, the present work aims at reviewing the current knowledge on the chronic inflammatory status and the altered immune/inflammatory functions in RTT, as well as investigating the emerging mechanisms underlying this condition with a special focus on the latest findings about inflammasome system, autoimmunity responses and intestinal micro- and mycobiota. On these bases, although further research is needed, future therapeutic strategies able to re-establish an adequate immune/inflammatory response could represent potential approaches for RTT patients.
Topics: Rett Syndrome; Humans; Inflammation; Inflammasomes; Methyl-CpG-Binding Protein 2; Animals; Gastrointestinal Microbiome
PubMed: 38815782
DOI: 10.1016/j.abb.2024.110046 -
International Journal of Molecular... Aug 2023Mitochondria, far beyond their prominent role as cellular powerhouses, are complex cellular organelles active as central metabolic hubs that are capable of integrating... (Review)
Review
Mitochondria, far beyond their prominent role as cellular powerhouses, are complex cellular organelles active as central metabolic hubs that are capable of integrating and controlling several signaling pathways essential for neurological processes, including neurogenesis and neuroplasticity. On the other hand, mitochondria are themselves regulated from a series of signaling proteins to achieve the best efficiency in producing energy, in establishing a network and in performing their own de novo synthesis or clearance. Dysfunctions in signaling processes that control mitochondrial biogenesis, dynamics and bioenergetics are increasingly associated with impairment in brain development and involved in a wide variety of neurodevelopmental disorders. Here, we review recent evidence proving the emerging role of mitochondria as master regulators of brain bioenergetics, highlighting their control skills in brain neurodevelopment and cognition. We analyze, from a mechanistic point of view, mitochondrial bioenergetic dysfunction as causally interrelated to the origins of typical genetic intellectual disability-related neurodevelopmental disorders, such as Down, Rett and Fragile X syndromes. Finally, we discuss whether mitochondria can become therapeutic targets to improve brain development and function from a holistic perspective.
PubMed: 37569863
DOI: 10.3390/ijms241512488 -
Proceedings of the National Academy of... Feb 2024Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that...
Rett syndrome (RTT) is a devastating neurodevelopmental disorder primarily caused by mutations in the methyl-CpG binding protein 2 (Mecp2) gene. Here, we found that inhibition of Receptor-Interacting Serine/Threonine-Protein Kinase 1 (RIPK1) kinase ameliorated progression of motor dysfunction after onset and prolonged the survival of Mecp2-null mice. Microglia were activated early in myeloid Mecp2-deficient mice, which was inhibited upon inactivation of RIPK1 kinase. RIPK1 inhibition in Mecp2-deficient microglia reduced oxidative stress, cytokines production and induction of SLC7A11, SLC38A1, and GLS, which mediate the release of glutamate. Mecp2-deficient microglia release high levels of glutamate to impair glutamate-mediated excitatory neurotransmission and promote increased levels of GluA1 and GluA2/3 proteins in vivo, which was reduced upon RIPK1 inhibition. Thus, activation of RIPK1 kinase in Mecp2-deficient microglia may be involved both in the onset and progression of RTT.
Topics: Animals; Mice; Glutamic Acid; Inflammation; Methyl-CpG-Binding Protein 2; Mice, Knockout; Microglia; Rett Syndrome
PubMed: 38289948
DOI: 10.1073/pnas.2320383121 -
Children (Basel, Switzerland) Aug 2023Pathogenic loss-of-function variants in the IQ motif and SEC7 domain containing protein 2 () gene cause intellectual disability with Rett syndrome (RTT)-like features....
Pathogenic loss-of-function variants in the IQ motif and SEC7 domain containing protein 2 () gene cause intellectual disability with Rett syndrome (RTT)-like features. The aim of this study was to obtain systematic information on the natural history and extra-central nervous system (CNS) manifestations for the Italian population (>90%) by using structured family interviews and semi-quantitative questionnaires. encephalopathy prevalence estimate was 7.0 to 7.9 × 10. Criteria for typical RTT were met in 42.1% of the cases, although psychomotor regression was occasionally evidenced. Genetic diagnosis was occasionally achieved in infancy despite a clinical onset before the first 24 months of life. High severity in both the CNS and extra-CNS manifestations for the patients was documented and related to a consistently adverse quality of life. Neurodevelopmental delay was diagnosed before the onset of epilepsy by 1.8 to 2.4 years. An earlier age at menarche in female patients was reported. Sleep disturbance was highly prevalent (60 to 77.8%), with mandatory co-sleeping behavior (50% of the female patients) being related to de novo variant origin, younger age, taller height with underweight, better social interaction, and lower life quality impact for the family and friends area. In conclusion, the encephalopathy is a rare and likely underdiagnosed developmental encephalopathy leading to an adverse life quality impact.
PubMed: 37761403
DOI: 10.3390/children10091442