Pathophysiological Mechanisms in Neurodevelopmental Disorders Caused by Rac GTPases Dysregulation: What's behind Neuro-RACopathies.
Ontology highlight
ABSTRACT:
SUBMITTER: Scala M
PROVIDER: S-EPMC8699292 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The 20-60 μm axon initial segment (AIS) is proximally located at the interface between the axon and cell body. AIS has characteristic molecular and structural properties regulated by the crucial protein, ankyrin-G. The AIS contains a high density of Na+ channels relative to the cell body, which allows low thresholds for the initiation of action potential (AP). Molecular and physiological studies have shown that the AIS is also a key domain for the control of neuronal excitability by homeostatic mechanisms. The AIS has high plasticity in normal developmental processes and pathological activities, such as injury, neurodegeneration, and neurodevelopmental disorders (NDDs). In the first half of this review, we provide an overview of the molecular, structural, and ion-channel characteristics of AIS, AIS regulation through axo-axonic synapses, and axo-glial interactions. In the second half, to understand the relationship between NDDs and AIS, we discuss the activity-dependent plasticity of AIS, the human mutation of AIS regulatory genes, and the pathophysiological role of an abnormal AIS in NDD model animals and patients. We propose that the AIS may provide a potentially valuable structural biomarker in response to abnormal network activity in vivo as well as a new treatment concept at the neural circuit level.
| S-EPMC8392614 | biostudies-literature
Project description:Genomic studies are increasingly revealing that neurodevelopmental disorders are caused by underlying genomic alterations. Chromosomal microarray testing has been used to reliably detect minute changes in genomic copy numbers. The genes located in the aberrated regions identified in patients with neurodevelopmental disorders may be associated with the phenotypic features. In such cases, haploinsufficiency is considered to be the mechanism, when the deletion of a gene is related to neurodevelopmental delay. The loss-of-function mutation in such genes may be evaluated using next-generation sequencing. On the other hand, the patients with increased copy numbers of the genes may exhibit different clinical symptoms compared to those with loss-of-function mutation in the genes. In such cases, the additional copies of the genes are considered to have a dominant negative effect, inducing cell stress. In other cases, not the copy number changes, but mutations of the genes are responsible for causing the clinical symptoms. This can be explained by the dominant negative effects of the gene mutations. Currently, the diagnostic yield of genomic alterations using comprehensive analysis is less than 50%, indicating the existence of more subtle alterations or genomic changes in the untranslated regions. Copy-neutral inversions and insertions may be related. Hence, better analytical algorithms specialized for the detection of such alterations are required for higher diagnostic yields.
| S-EPMC8470284 | biostudies-literature
Project description:BackgroundMotor abnormalities (MAs) of severe mental disorders have been traditionally neglected both in clinical practice and research, although they are an increasing focus of attention because of their clinical and neurobiological relevance. For historical reasons, most of the literature on MAs has been focused to a great extent on schizophrenia, and as a consequence their prevalence and featural properties in other psychiatric or neuropsychiatric disorders are poorly known. In this article, we evaluated the extent to which catatonic, extrapyramidal and neurological soft signs, and their associated clinical features, are present transdiagnostically.MethodsWe examined motor-related features in neurodevelopmental (schizophrenia, obsessive compulsive disorder, autism spectrum disorders), "functional" (nonschizophrenic nonaffective psychoses, mood disorders) and neurodegenerative (Alzheimer's disease) disorders. Examination of the literature revealed that there have been very few comparisons of motor-related features across diagnoses and we had to rely mainly in disorder-specific studies to compare it transdiagnostically.ResultsOne or more motor domains had a substantial prevalence in all the diagnoses examined. In "functional" disorders, MAs, and particularly catatonic signs, appear to be markers of episode severity; in chronic disorders, although with different degree of strength or evidence, all motor domains are indicators of both disorder severity and poor outcome; lastly, in Alzheimer's disease they are also indicators of disorder progression.ConclusionsMAs appear to represent a true transdiagnostic domain putatively sharing neurobiological mechanisms of neurodevelopmental, functional or neurodegenerative origin.
| S-EPMC5581892 | biostudies-literature
Project description:Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
| S-EPMC7895900 | biostudies-literature
Project description:Over thirty years have passed since the first description of ubiquitin-positive structures in the brain of patients suffering from Alzheimer's disease. Meanwhile, the intracellular accumulation of ubiquitin-modified insoluble protein aggregates has become an indisputable hallmark of neurodegeneration. However, the role of ubiquitin and a fortiori the ubiquitin-proteasome system (UPS) in the pathogenesis of neurodevelopmental disorders (NDD) is much less described. In this article, we review all reported monogenic forms of NDD caused by lesions in genes coding for any component of the UPS including ubiquitin-activating (E1), -conjugating (E2) enzymes, ubiquitin ligases (E3), ubiquitin hydrolases, and ubiquitin-like modifiers as well as proteasome subunits. Strikingly, our analysis revealed that a vast majority of these proteins have a described function in the negative regulation of the innate immune response. In this work, we hypothesize a possible involvement of autoinflammation in NDD pathogenesis. Herein, we discuss the parallels between immune dysregulation and neurodevelopment with the aim at improving our understanding the biology of NDD and providing knowledge required for the design of novel therapeutic strategies.
| S-EPMC8455891 | biostudies-literature
Project description:HACE1 is an E3 ubiquitin ligase with important roles in tumor biology and tissue homeostasis. Loss or mutation of HACE1 has been associated with the occurrence of a variety of neoplasms, but the underlying mechanisms have not been defined yet. Here we report that HACE1 is frequently mutated in human lung cancer. In mice, loss of Hace1 led to enhanced progression of KRasG12D-driven lung tumors. Additional ablation of the oncogenic GTPase Rac1 partially reduced progression of Hace1-/- lung tumors. RAC2, a novel ubiquitylation target of HACE1, could compensate for the absence of its homolog RAC1 in Hace1-deficient, but not in HACE1-sufficient tumors. Accordingly, ablation of both Rac1 and Rac2 fully averted the increased progression of KRasG12D-driven lung tumors in Hace1-/- mice. In lung cancer patients, increased expression of HACE1 correlated with reduced levels of RAC1 and RAC2 and prolonged survival, while elevated expression of RAC1 and RAC2 was associated with poor prognosis. This work defines HACE1 as a crucial regulator of the oncogenic activity of RAC-family GTPases in lung cancer development.
2020-04-27 | GSE149137 | GEO
Project description:The combined knowledge of word meanings and grammatical rules does not allow a listener to grasp the intended meaning of a speaker's utterance. Pragmatic inferences on the part of the listener are also required. The present work focuses on the processing of ironic utterances (imagine a slow day being described as "really productive") because these clearly require the listener to go beyond the linguistic code. Such utterances are advantageous experimentally because they can serve as their own controls in the form of literal sentences (now imagine an active day being described as "really productive") as we employ techniques from electrophysiology (EEG). Importantly, the results confirm previous ERP findings showing that irony processing elicits an enhancement of the P600 component (Regel et al., 2011). More original are the findings drawn from Time Frequency Analysis (TFA) and especially the increase of power in the gamma band in the 280-400 time-window, which points to an integration among different streams of information relatively early in the comprehension of an irony. This represents a departure from traditional accounts of language processing which generally view pragmatic inferences as late-arriving. We propose that these results indicate that unification operations between the linguistic code and contextual information play a critical role throughout the course of irony processing and earlier than previously thought.
| S-EPMC3691266 | biostudies-literature
Project description:Importance:Knowing the range of symptoms seen in patients with a missense or loss-of-function variant in KCNB1 and how these symptoms correlate with the type of variant will help clinicians with diagnosis and prognosis when treating new patients. Objectives:To investigate the clinical spectrum associated with KCNB1 variants and the genotype-phenotype correlations. Design, Setting, and Participants:This study summarized the clinical and genetic information of patients with a presumed pathogenic variant in KCNB1. Patients were identified in research projects or during clinical testing. Information on patients from previously published articles was collected and authors contacted if feasible. All patients were seen at a clinic at one of the participating institutes because of presumed genetic disorder. They were tested in a clinical setting or included in a research project. Main Outcomes and Measures:The genetic variant and its inheritance and information on the patient's symptoms and characteristics in a predefined format. All variants were identified with massive parallel sequencing and confirmed with Sanger sequencing in the patient. Absence of the variant in the parents could be confirmed with Sanger sequencing in all families except one. Results:Of 26 patients (10 female, 15 male, 1 unknown; mean age at inclusion, 9.8 years; age range, 2-32 years) with developmental delay, 20 (77%) carried a missense variant in the ion channel domain of KCNB1, with a concentration of variants in region S5 to S6. Three variants that led to premature stops were located in the C-terminal and 3 in the ion channel domain. Twenty-one of 25 patients (84%) had seizures, with 9 patients (36%) starting with epileptic spasms between 3 and 18 months of age. All patients had developmental delay, with 17 (65%) experiencing severe developmental delay; 14 (82%) with severe delay had behavioral problems. The developmental delay was milder in 4 of 6 patients with stop variants and in a patient with a variant in the S2 transmembrane element rather than the S4 to S6 region. Conclusions and Relevance:De novo KCNB1 missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminal likely cause neurodevelopmental disorders with or without seizures. Patients with presumed pathogenic variants in KCNB1 have a variable phenotype. However, the type and position of the variants in the protein are (imperfectly) correlated with the severity of the disorder.
| S-EPMC5710242 | biostudies-literature
Project description:The formation and maturation of the human brain is regulated by highly coordinated developmental events, such as neural cell proliferation, migration and differentiation. Any impairment of these interconnected multi-factorial processes can affect brain structure and function and lead to distinctive neurodevelopmental disorders. Here, we review the pathophysiology of the Bosch-Boonstra-Schaaf Optic Atrophy Syndrome (BBSOAS; OMIM 615722; ORPHA 401777), a recently described monogenic neurodevelopmental syndrome caused by the haploinsufficiency of NR2F1 gene, a key transcriptional regulator of brain development. Although intellectual disability, developmental delay and visual impairment are arguably the most common symptoms affecting BBSOAS patients, multiple additional features are often reported, including epilepsy, autistic traits and hypotonia. The presence of specific symptoms and their variable level of severity might depend on still poorly characterized genotype-phenotype correlations. We begin with an overview of the several mutations of NR2F1 identified to date, then further focuses on the main pathological features of BBSOAS patients, providing evidence-whenever possible-for the existing genotype-phenotype correlations. On the clinical side, we lay out an up-to-date list of clinical examinations and therapeutic interventions recommended for children with BBSOAS. On the experimental side, we describe state-of-the-art in vivo and in vitro studies aiming at deciphering the role of mouse Nr2f1, in physiological conditions and in pathological contexts, underlying the BBSOAS features. Furthermore, by modeling distinct NR2F1 genetic alterations in terms of dimer formation and nuclear receptor binding efficiencies, we attempt to estimate the total amounts of functional NR2F1 acting in developing brain cells in normal and pathological conditions. Finally, using the NR2F1 gene and BBSOAS as a paradigm of monogenic rare neurodevelopmental disorder, we aim to set the path for future explorations of causative links between impaired brain development and the appearance of symptoms in human neurological syndromes.
| S-EPMC9024734 | biostudies-literature
Project description:Development of the mammalian inner ear requires coordination of cell proliferation, cell fate determination and morphogenetic movements. While significant progress has been made in identifying developmental signals required for inner ear formation, less is known about how distinct signals are coordinated by their downstream mediators. Members of the Rac family of small GTPases are known regulators of cytoskeletal remodeling and numerous other cellular processes. However, the function of Rac GTPases in otic development is largely unexplored. Here, we show that Rac1 and Rac3 redundantly regulate many aspects of inner ear morphogenesis. While no morphological defects were observed in Rac3(-/-) mice, Rac1(CKO); Rac3(-/-) double mutants displayed enhanced vestibular and cochlear malformations compared to Rac1(CKO) single mutants. Moreover, in Rac1(CKO); Rac3(-/-) mutants, we observed compromised E-cadherin-mediated cell adhesion, reduced cell proliferation and increased cell death in the early developing otocyst, leading to a decreased size and malformation of the membranous labyrinth. Finally, cochlear extension was severely disrupted in Rac1(CKO); Rac3(-/-) mutants, accompanied by a loss of epithelial cohesion and formation of ectopic sensory patches underneath the cochlear duct. The compartmentalized expression of otic patterning genes within the Rac1(CKO); Rac3(-/-) mutant otocyst was largely normal, however, indicating that Rac proteins regulate inner ear morphogenesis without affecting cell fate specification. Taken together, our results reveal an essential role for Rac GTPases in coordinating cell adhesion, cell proliferation, cell death and cell movements during otic development.
| S-EPMC3267834 | biostudies-literature