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Protein Kinases and Phosphatases in Neurodevelopmental Disorders

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 12104

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Dr. Chian Ju Jong

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Guest Editor

Department of Neuroscience and Pharmacology, Carver College of Medicine, University of Iowa, Iowa City, IA 52240, USA
Interests: taurine; cardiovascular diseases; neurodevelopmental disorders; neurodegenerative diseases; protein phosphatases

Special Issue Information

Dear Colleagues,

Protein kinases and phosphatases are two key enzymes that phosphorylate and dephosphorylate proteins, respectively. In general, a suitable balance between the actions of protein kinases and phosphatases is essential in regulating a multitude of cellular signaling processes in neuronal development. As a result, an imbalance between the actions of kinases and phosphatases may lead to hyper- or hypophosphorylation of proteins and alter the downstream cellular signaling cascades that regulate normal cellular functions. Pathologies such as cardiovascular diseases, cancer, neurodegenerative diseases, neurodevelopmental disorders, metabolic diseases and aging have been associated with deregulation of cellular signaling caused by impaired activity of kinases and/or phosphatases. This Special Issue will cover a selection of original articles and reviews focusing on various pathologies caused by deregulation of the activity of kinases or phosphatases, where the underlying mechanisms of dysregulation will be discussed.

Dr. Chian Ju Jong
Guest Editor

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Keywords

kinases
phosphatases
neurodevelopmental disorders
neuronal development
neuronal signaling pathways

Published Papers (4 papers)

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Research

16 pages, 2029 KiB

Open AccessArticle

An Epilepsy-Associated Mutation of Salt-Inducible Kinase 1 Increases the Susceptibility to Epileptic Seizures and Interferes with Adrenocorticotropic Hormone Therapy for Infantile Spasms in Mice

by Bo Pang, Takuma Mori, Moataz Badawi, Mengyun Zhou, Qi Guo, Emi Suzuki-Kouyama, Toru Yanagawa, Yoshinori Shirai and Katsuhiko Tabuchi

Int. J. Mol. Sci. 2022, 23(14), 7927; https://doi.org/10.3390/ijms23147927 - 18 Jul 2022

Cited by 9 | Viewed by 2444

Abstract

Six mutations in the salt-inducible kinase 1 (SIK1) have been identified in developmental and epileptic encephalopathy (DEE-30) patients, and two of the mutations are nonsense mutations that truncate the C-terminal region of SIK1. In a previous study, we generated SIK1 mutant (SIK1-MT) mice recapitulating the C-terminal truncated mutations using CRISPR/Cas9-mediated genome editing and found an increase in excitatory synaptic transmission and enhancement of neural excitability in neocortical neurons in SIK1-MT mice. NMDA was injected into SIK1-MT males to induce epileptic seizures in the mice. The severity of the NMDA-induced seizures was estimated by the latency and the number of tail flickering and hyperflexion. Activated brain regions were evaluated by immunohistochemistry against c-fos, Iba1, and GFAP. As another epilepsy model, pentylenetetrazol was injected into the adult SIK1 mutant mice. Seizure susceptibility induced by both NMDA and PTZ was enhanced in SIK1-MT mice. Brain regions including the thalamus and hypothalamus were strongly activated in NMDA-induced seizures. The epilepsy-associated mutation of SIK1 canceled the pharmacological effects of the ACTH treatment on NMDA-induced seizures. These results suggest that SIK1 may be involved in the neuropathological mechanisms of NMDA-induced spasms and the pharmacological mechanism of ACTH treatment. Full article

(This article belongs to the Special Issue Protein Kinases and Phosphatases in Neurodevelopmental Disorders)

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17 pages, 3594 KiB

Open AccessArticle

Haploinsufficiency of a Circadian Clock Gene Bmal1 (Arntl or Mop3) Causes Brain-Wide mTOR Hyperactivation and Autism-like Behavioral Phenotypes in Mice

by Rubal Singla, Abhishek Mishra, Hao Lin, Ethan Lorsung, Nam Le, Su Tin, Victor X. Jin and Ruifeng Cao

Int. J. Mol. Sci. 2022, 23(11), 6317; https://doi.org/10.3390/ijms23116317 - 5 Jun 2022

Cited by 13 | Viewed by 4341

Abstract

Approximately 50–80% of children with autism spectrum disorders (ASDs) exhibit sleep problems, but the contribution of circadian clock dysfunction to the development of ASDs remains largely unknown. The essential clock gene Bmal1 (Arntl or Mop3) has been associated with human sociability, and its missense mutation is found in ASD. Our recent study found that Bmal1-null mice exhibit a variety of autism-like phenotypes. Here, we further investigated whether an incomplete loss of Bmal1 function could cause significant autism-like behavioral changes in mice. Our results demonstrated that heterozygous Bmal1 deletion (Bmal1^+/−) reduced the Bmal1 protein levels by ~50–75%. Reduced Bmal1 expression led to decreased levels of clock proteins, including Per1, Per2, Cry 1, and Clock but increased mTOR activities in the brain. Accordingly, Bmal1^+/− mice exhibited aberrant ultrasonic vocalizations during maternal separation, deficits in sociability and social novelty, excessive repetitive behaviors, impairments in motor coordination, as well as increased anxiety-like behavior. The novel object recognition memory remained intact. Together, these results demonstrate that haploinsufficiency of Bmal1 can cause autism-like behavioral changes in mice, akin to those identified in Bmal1-null mice. This study provides further experimental evidence supporting a potential role for disrupted clock gene expression in the development of ASD. Full article

(This article belongs to the Special Issue Protein Kinases and Phosphatases in Neurodevelopmental Disorders)

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23 pages, 38651 KiB

Open AccessArticle

Inhibition of Neuronal Necroptosis Mediated by RIPK1 Provides Neuroprotective Effects on Hypoxia and Ischemia In Vitro and In Vivo

by Elena V. Mitroshina, Maria M. Loginova, Roman S. Yarkov, Mark D. Urazov, Maria O. Novozhilova, Mikhail I. Krivonosov, Mikhail V. Ivanchenko and Maria V. Vedunova

Int. J. Mol. Sci. 2022, 23(2), 735; https://doi.org/10.3390/ijms23020735 - 10 Jan 2022

Cited by 10 | Viewed by 2267

Abstract

Ischemic brain injury is a widespread pathological condition, the main components of which are a deficiency of oxygen and energy substrates. In recent years, a number of new forms of cell death, including necroptosis, have been described. In necroptosis, a cascade of interactions between the kinases RIPK1 and RIPK3 and the MLKL protein leads to the formation of a specialized death complex called the necrosome, which triggers MLKL-mediated destruction of the cell membrane and necroptotic cell death. Necroptosis probably plays an important role in the development of ischemia/reperfusion injury and can be considered as a potential target for finding methods to correct the disruption of neural networks in ischemic damage. In the present study, we demonstrated that blockade of RIPK1 kinase by Necrostatin-1 preserved the viability of cells in primary hippocampal cultures in an in vitro model of glucose deprivation. The effect of RIPK1 blockade on the bioelectrical and metabolic calcium activity of neuron-glial networks in vitro using calcium imaging and multi-electrode arrays was assessed for the first time. RIPK1 blockade was shown to partially preserve both calcium and bioelectric activity of neuron-glial networks under ischemic factors. However, it should be noted that RIPK1 blockade does not preserve the network parameters of the collective calcium dynamics of neuron-glial networks, despite the maintenance of network bioelectrical activity (the number of bursts and the number of spikes in the bursts). To confirm the data obtained in vitro, we studied the effect of RIPK1 blockade on the resistance of small laboratory animals to in vivo modeling of hypoxia and cerebral ischemia. The use of Necrostatin-1 increases the survival rate of C57BL mice in modeling both acute hypobaric hypoxia and ischemic brain damage. Full article

(This article belongs to the Special Issue Protein Kinases and Phosphatases in Neurodevelopmental Disorders)

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21 pages, 14964 KiB

Open AccessArticle

Molecular Modeling Studies of N-phenylpyrimidine-4-amine Derivatives for Inhibiting FMS-like Tyrosine Kinase-3

by Suparna Ghosh, Seketoulie Keretsu and Seung Joo Cho

Int. J. Mol. Sci. 2021, 22(22), 12511; https://doi.org/10.3390/ijms222212511 - 19 Nov 2021

Cited by 7 | Viewed by 2007

Abstract

Overexpression and frequent mutations in FMS-like tyrosine kinase-3 (FLT3) are considered risk factors for severe acute myeloid leukemia (AML). Hyperactive FLT3 induces premature activation of multiple intracellular signaling pathways, resulting in cell proliferation and anti-apoptosis. We conducted the computational modeling studies of 40 pyrimidine-4,6-diamine-based compounds by integrating docking, molecular dynamics, and three-dimensional structure–activity relationship (3D-QSAR). Molecular docking showed that K644, C694, F691, E692, N701, D829, and F830 are critical residues for the binding of ligands at the hydrophobic active site. Molecular dynamics (MD), together with Molecular Mechanics Poison–Boltzmann/Generalized Born Surface Area, i.e., MM-PB(GB)SA, and linear interaction energy (LIE) estimation, provided critical information on the stability and binding affinity of the selected docked compounds. The MD study suggested that the mutation in the gatekeeper residue F691 exhibited a lower binding affinity to the ligand. Although, the mutation in D835 in the activation loop did not exhibit any significant change in the binding energy to the most active compound. We developed the ligand-based comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) models. CoMFA (q² = 0.802, r² = 0.983, and

Q_{F 3}^{2}

= 0.698) and CoMSIA (q² = 0.725, r² = 0.965 and

Q_{F 3}^{2}

= 0.668) established the structure–activity relationship (SAR) and showed a reasonable external predictive power. The contour maps from the CoMFA and CoMSIA models could explain valuable information about the favorable and unfavorable positions for chemical group substitution, which can increase or decrease the inhibitory activity of the compounds. In addition, we designed 30 novel compounds, and their predicted pIC₅₀ values were assessed with the CoMSIA model, followed by the assessment of their physicochemical properties, bioavailability, and free energy calculation. The overall outcome could provide valuable information for designing and synthesizing more potent FLT3 inhibitors. Full article

(This article belongs to the Special Issue Protein Kinases and Phosphatases in Neurodevelopmental Disorders)

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