Neuroscience
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Two major processes tightly regulate protein synthesis, the initiation of mRNA translation and elongation phase that mediates the movement of ribosomes along the mRNA. The elongation phase is a high energy-consuming process, and is mainly regulated by the eukaryotic elongation factor 2 kinase (eEF2K) activity that phosphorylates and inhibits eEF2, the only known substrate of the kinase. eEF2K activity is closely regulated by several signaling pathways because the translation elongation phase strongly influences the cellular energy demand and can change the expression of specific proteins in different tissues. An increasing number of recent findings link eEF2k over activation to an array of human diseases, such as atherosclerosis, pulmonary arterial hypertension, progression of solid tumors, and some major neurological disorders. ⋯ Therefore, it is possible to postulate that inhibiting its function may not cause serious side effects. In addition, eEF2K is a peculiar kinase molecularly different from most of other mammalian kinases and new compounds that inhibit eEF2K should not necessarily interfere with other important protein kinases. In this review we will critically summarize the evidence supporting the role of the altered eEF2K/eEF2 pathway in defined neurological diseases and its implications in curing these diseases in animal models, and possibly in humans, by targeting eEF2K activity.
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Neurodevelopmental disorders (NDDs) include a large number of conditions such as Fragile X syndrome, autism spectrum disorders and Down syndrome, among others. They are characterized by limitations in adaptive and social behaviors, as well as intellectual disability (ID). Whole-exome and whole-genome sequencing studies have highlighted a large number of NDD/ID risk genes. ⋯ The fruit fly, Drosophila melanogaster, is an ideal model to study NDDs, with highly tractable genetics, combined with simple behavioral and circuit assays, permitting rapid medium-throughput screening of NDD/ID risk genes. Here, we review studies where the use of well-established assays to study mechanisms of learning and memory in Drosophila has permitted insights into molecular mechanisms underlying IDs. We discuss how technologies in the fly model, combined with a high degree of molecular and physiological conservation between flies and mammals, highlight the Drosophila system as an ideal model to study neurodevelopmental disorders, from genetics to behavior.
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Mutations in the CDKL5 (cyclin-dependent kinase-like 5) gene cause CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental syndrome where patients exhibit early-onset seizures, intellectual disability, stereotypies, limited or absent speech, autism-like symptoms and sensory impairments. Mounting evidences indicate that disrupted sensory perception and processing represent core signs also in mouse models of CDD; however we have very limited knowledge on their underlying causes. In this study, we investigated how CDKL5 deficiency affects synaptic organization and experience-dependent plasticity in the thalamo-cortical (TC) pathway carrying whisker-related tactile information to the barrel cortex (BC). ⋯ Notably, a 2-day paradigm of enriched whisker stimulation rescued both number and configuration of excitatory synapses in Cdkl5-KO mice, restored cortical activity and normalized behavioral responses to wild-type mice levels. Our findings disclose a novel and unsuspected role of CDKL5 in controlling the organization and experience-induced modifications of excitatory connections in the BC and indicate how mutations of CDKL5 produce failures in higher-order processing of somatosensory stimuli. This article is part of a Special Issue entitled: Animal Models of Neurodevelopmental Disorders.
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The UBE3A gene is part of the chromosome 15q11-q13 region that is frequently deleted or duplicated, leading to several neurodevelopmental disorders (NDD). Angelman syndrome (AS) is caused by the absence of functional maternally derived UBE3A protein, while the paternal UBE3A gene is present but silenced specifically in neurons. Patients with AS present with severe neurodevelopmental delay, with pronounced motor deficits, absence of speech, intellectual disability, epilepsy, and sleep problems. ⋯ Inducible AS mouse models have helped to identify the critical treatment windows for the behavioral and physiological phenotypes. Additionally, AS mouse models indicate an important role for the predominantly nuclear UBE3A isoform in generating the characteristic AS pathology. Last, but not least, the AS mice have been crucial in guiding Ube3a gene reactivation treatments, which present a very promising therapy to treat AS.
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Angelman syndrome is a neurodevelopmental disorder presenting with severe deficits in motor, speech, and cognitive abilities. The primary genetic cause of Angelman syndrome is a maternally transmitted mutation in the Ube3a gene, which has been successfully modeled in Ube3a mutant mice. Phenotypes have been extensively reported in young adult Ube3a mice. ⋯ Reduced general exploratory locomotion at this age prevented the interpretation of an anxiety-like phenotype, and likely impacted social tasks. Robust phenotypes in middle-aged Ube3a mice appear to result from continued motor decline. Motor deficits may provide the best outcome measures for preclinical testing of pharmacological targets, towards reductions of symptoms in adults with Angelman syndrome.