CDKL5 Gene: Beyond Rett Syndrome

2021 ◽  
Author(s):  
Lina Maria Ciccia ◽  
Bruna Scalia ◽  
Valeria Venti ◽  
Francesco Pizzo ◽  
Maria Grazia Pappalardo ◽  
...  
Keyword(s):  
Motor Development ◽  
Synapse Formation ◽  
Drug Resistant ◽  
Therapeutic Approaches ◽  
Serine Threonine Kinase ◽  
Ataxic Gait ◽  
Actual Knowledge ◽  
Threonine Kinase ◽  
Axon Development ◽  
Development Delay

Abstract CDKL5 is a gene located in the X-chromosome (Xp22) encoding a serine/threonine kinase involved in various signaling pathways, implicated in cell proliferation, axon development, dendrite growth, synapse formation, and maintenance. Mutations occurring in this gene have been associated with drug-resistant early-onset epilepsy, with multiple seizures type, and deep cognitive and motor development delay with poor or absent speech, ataxic gait or inability to walk, hand stereotypies and in a few cases decrement of head growth. Many aspects remain unclear about the CDKL5 deficiency disorders, research will be fundamental to better understand the pathogenesis of neurological damage and consequently developed more targeted and profitable therapies, as there is not, at the present, a gene-based treatment and the seizures are in most of the cases drug resistant. In this article, we summarize the actual knowledge about CDKL5 gene function and mostly the consequence given by its dysfunction, also examining the possible therapeutic approaches.

scholarly journals Longitudinal Evaluation of Cerebellar Signs of H-ABC Tubulinopathy in a Patient and in the taiep Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Milvia Alata ◽  
Arturo González-Vega ◽  
Valeria Piazza ◽  
Anke Kleinert-Altamirano ◽  
Carmen Cortes ◽  
...  
Keyword(s):  
White Matter ◽  
Basal Ganglia ◽  
Cognitive Deficits ◽  
Motor Development ◽  
Clinical Signs ◽  
Ventricular System ◽  
Ataxic Gait ◽  
White Matter Changes ◽  
Abnormal Movements ◽  
Development Delay

Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) is a central neurodegenerative disease due to mutations in the tubulin beta-4A (TUBB4A) gene, characterized by motor development delay, abnormal movements, ataxia, spasticity, dysarthria, and cognitive deficits. Diagnosis is made by integrating clinical data and radiological signs. Differences in MRIs have been reported in patients that carry the same mutation; however, a quantitative study has not been performed so far. Our study aimed to provide a longitudinal analysis of the changes in the cerebellum (Cb), corpus callosum (CC), ventricular system, and striatum in a patient suffering from H-ABC and in the taiep rat. We correlated the MRI signs of the patient with the results of immunofluorescence, gait analysis, segmentation of cerebellum, CC, and ventricular system, performed in the taiep rat. We found that cerebellar and callosal changes, suggesting a potential hypomyelination, worsened with age, in concomitance with the emergence of ataxic gait. We also observed a progressive lateral ventriculomegaly in both patient and taiep, possibly secondary to the atrophy of the white matter. These white matter changes are progressive and can be involved in the clinical deterioration. Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) gives rise to a spectrum of clinical signs whose pathophysiology still needs to be understood.

scholarly journals Protein Kinase KIS Localizes to RNA Granules and Enhances Local Translation

2008 ◽  
Vol 29 (3) ◽  
pp. 726-735 ◽  
Author(s):  
Serafí Cambray ◽  
Neus Pedraza ◽  
Marta Rafel ◽  
Eloi Garí ◽  
Martí Aldea ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Molecular Mechanisms ◽  
Local Translation ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Rna Granules ◽  
Axon Development ◽  
Brain Extracts ◽  
Cultured Cortical Neurons ◽  
Actin Mrna

ABSTRACT The regulation of mRNA transport is a fundamental process for cytoplasmic sorting of transcripts and spatially controlled translational derepression once properly localized. There is growing evidence that translation is locally modulated as a result of specific synaptic inputs. However, the underlying molecular mechanisms that regulate this translational process are just emerging. We show that KIS, a serine/threonine kinase functionally related to microtubule dynamics and axon development, interacts with three proteins found in RNA granules: KIF3A, NonO, and eEF1A. KIS localizes to RNA granules and colocalizes with the KIF3A kinesin and the β-actin mRNA in cultured cortical neurons. In addition, KIS is found associated with KIF3A and 10 RNP-transported mRNAs in brain extracts. The results of knockdown experiments indicate that KIS is required for normal neurite outgrowth. More important, the kinase activity of KIS stimulates 3′ untranslated region-dependent local translation in neuritic projections. We propose that KIS is a component of the molecular device that modulates translation in RNA-transporting granules as a result of local signals.

scholarly journals Inhibition of ULK2 Autophagic Activity by Its Association with YAP

2016 ◽  
Vol 8 (1) ◽  
pp. 12 ◽  
Author(s):  
Sung Hwa Shin ◽  
Eun Jeoung Lee ◽  
Sunghee Hyun ◽  
Dowonkyoung Park ◽  
Sang Sun Kang
Keyword(s):  
Mammalian Cells ◽  
Signal Transduction Pathway ◽  
Transduction Pathway ◽  
Wild Type ◽  
Therapeutic Approaches ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Py Motif

Uncoordinated 51-like kinase 2 (ULK2) is a member of the serine/threonine kinase family that functions an essential role regulating autophagy in mammalian cells. As autophagy is implicated in normal cellular homeostasis and multiple diseases, better mechanisticinsight will drive thedevelopment of novel therapeutic approaches. Here, we present evidence that ULK2 interacts withYAP for its degradation and subcellular localization. A potential PPxY motif (328PPnY331) was identified, which is similar with the consensus PPxY motif in ULK2 S/P domain. TheP329A (PA) mutation in the PY motif of ULK2 abolished the YAP-ULK2 association.At first, we observed that ULK2 physically interacted to YAP in vivo and in vitro, using a pull-down approach. Secondly, ULK2 and YAP co- localized at the apical (or tight junction) membrane as visualized by confocal microscopy. Furthermore, the PA mutant substantially increased during autophagy than that of wild-type ULK2 or the P242A mutant in transient transfection assays. Thus, the association between ULK2 and YAP through the WW domain links autophagy and the Hippo signal transduction pathway.

GSK-3 Inhibitors as New Leads to Treat Type-II Diabetes

2021 ◽  
Vol 22 ◽  
Author(s):  
Gangarapu Kiran ◽  
Gowru Srivani ◽  
Prabhakar Reddy Veerareddy ◽  
Ramyakrishna Sharvirala ◽  
Dilipkumar Pal
Keyword(s):  
Type Ii Diabetes ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase 3 ◽  
Type Ii ◽  
Therapeutic Approaches ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Dpp Iv ◽  
Treatment Of Diabetes

In India as well as globally diabetes is in a state of high risk and only next to cardiovascular disease. As per the WHO the risk of diabetes is expected to rise to about 511 million by 2030. In quest for novel targets for type-2 diabetes many targets were elucidated such as Glycogen Synthase Kinase-3 (GSK-3), Dipeptidyl Peptidase (DPP-IV), PPAR-, α-Glucosidase, α-Amylase, GLP-1, SGLT. Among the targets GSK-3 reported to be an effective target for the treatment of diabetes. In the metabolism of glycogen, GSK is a regulating enzyme for the biosynthesis of glycogen (glycogenesis). It catalyzes the synthesis of linear unbranched molecule with 1,4-- glycosidic linkages. GSK-3 family has two isoenzymes, namely α and β which differ in their N- and C- terminal sequences and is a semi conservative multifunctional serine/threonine kinase enzyme. In this chapter we discuss an overview of general diabetic mechanisms and how GSK-3 modulation may influence these processes. Mutation in the GSK-3 complex that cause diabetes. Synthetic and natural scaffolds which modulates the GSK-3 against diabetes and lead optimization for the development of GSK-3 inhibitors. This review mainly focuses on the development of GSK-3 inhibitors and highlights current and potential future therapeutic approaches that supports the notion of targeting glucose metabolism with novel antidiabetic agents.

Physiologic Studies Provide New Perspectives on Early Speech Development

2010 ◽  
Vol 20 (2) ◽  
pp. 29-36
Author(s):  
Erin M. Wilson ◽  
Ignatius S. B. Nip
Keyword(s):  
Motor Control ◽  
Motor Development ◽  
Motion Tracking ◽  
Speech Development ◽  
Speech Motor Control ◽  
Therapeutic Approaches ◽  
Facial Motion ◽  
Disordered Speech ◽  
Speech Motor ◽  
Physiologic Data

Abstract Although certain speech development milestones are readily observable, the developmental course of speech motor control is largely unknown. However, recent advances in facial motion tracking systems have been used to investigate articulator movements in children and the findings from these studies are being used to further our understanding of the physiologic basis of typical and disordered speech development. Physiologic work has revealed that the emergence of speech is highly dependent on the lack of flexibility in the early oromotor system. It also has been determined that the progression of speech motor development is non-linear, a finding that has motivated researchers to investigate how variables such as oromotor control, cognition, and linguistic factors affect speech development in the form of catalysts and constraints. Physiologic data are also being used to determine if non-speech oromotor behaviors play a role in the development of speech. This improved understanding of the physiology underlying speech, as well as the factors influencing its progression, helps inform our understanding of speech motor control in children with disordered speech and provide a framework for theory-driven therapeutic approaches to treatment.

Ability of PknA, a mycobacterial eukaryotic-type serine/threonine kinase, to transphosphorylate MurD, a ligase involved in the process of peptidoglycan biosynthesis

2008 ◽  
Vol 415 (1) ◽  
pp. 27-33 ◽  
Author(s):  
Meghna Thakur ◽  
Pradip K. Chakraborti
Keyword(s):  
Protein Kinases ◽  
Solid Phase ◽  
Morphological Changes ◽  
Binding Assays ◽  
Serine Threonine Kinase ◽  
Threonine Kinase ◽  
Peptidoglycan Biosynthesis ◽  
Vitro Binding ◽  
Solid Phase Binding

Eukaryotic-type serine/threonine protein kinases in bacteria have been implicated in controlling a host of cellular activities. PknA is one of eleven such protein kinases from Mycobacterium tuberculosis which regulates morphological changes associated with cell division. In the present study we provide the evidence for the ability of PknA to transphosphorylate mMurD (mycobacterial UDP-N-acetylmuramoyl-L-alanine:D-glutamate-ligase), the enzyme involved in peptidoglycan biosynthesis. Its co-expression in Escherichia coli along with PknA resulted in phosphorylation of mMurD. Consistent with these observations, results of the solid-phase binding assays revealed a high-affinity in vitro binding between the two proteins. Furthermore, overexpression of m-murD in Mycobacterium smegmatis yielded a phosphorylated protein. The results of the present study therefore point towards the possibility of mMurD being a substrate of PknA.

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