Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A loss or shortening of dendritic spines has been described in patients with neurodegenerative disorders such as Alzheimer's disease, but the underlying mechanisms are poorly understood. Recently, there have been four reports of capture of the plus-ends of microtubules in the dendritic spines. One report, based on acute hippocampal slices that were fixed by a microtubule preserving process after LTP-inducing stimulation, showed that microtubules of the dendritic shaft ramified into spines in a manner that was specific to the stimulated postsynaptic membranes. This resulted in enlarged protrusion of the dendritic spines. Other reports using living cultured neurons, showed that growing microtubule plus-ends enter spines and modulate spine morphology. Since microtubules originate from the centrosome, these four reports strongly suggest a stimulation-dependent connection between the nucleus and the stimulated postsynaptic membrane by microtubules. Several pieces of evidence suggest that spine elongation may be caused by microtubule polymerization. Firstly, the entry of plus-ends of microtubules into spines accompanies spine enlargement. Further, microtubule-associated protein-1B is over-expressed in Fragile X syndrome, in which spines are much elongated. Chronic stress causes neurite outgrowth and spine elongation. Polymerization of microtubules caused neurite outgrowth and microtubules-depolymerizing agents neurite retraction, both consistent with the proposition that spine elongation is caused by microtubule polymerization. This structural mechanism for spine elongation suggests, conversely, that synapse loss or spine shortening observed in Alzheimer's disease may be caused by depolymerization of intraspinal microtubules. The fact that a new drug, dimebon, shows promising results against memory disturbance in Alzheimer's patients and can also cause neurite outgrowth in cultured neurons may also support this idea. Amyloid activates GSK-3beta and it causes the abnormal hyperphosphorylation of tau and depolymerization of axonal microtubules, resulting in the impairment of axonal transport. Normal tau is mainly present in the axon, but hyperphosphorylated tau newly distributes to the dendrites and sequesters normal tau, MAP1A/MAP1B and MAP2, and may cause disruption of intraspinal microtubules by losing the microtubule-preserving effect of MAPs. Nevertheless, it may be strongly suspected that amyloid beta may be a putative intra-spinal microtubule-depolymerizer to induce spine shortening, synaptic loss and finally the memory disturbance in Alzheimer's disease.
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PMID:Amyloid beta: a putative intra-spinal microtubule-depolymerizer to induce synapse-loss or dentritic spine shortening in Alzheimer's disease. 2019 23

Fragile X syndrome (FXS), one of the most common genetic causes of autism, results from a loss of fragile X mental retardation protein (FMRP) expression. At the molecular level, abnormal neurodevelopment is thought to result from dysregulated protein synthesis of key neural synaptic proteins, however recent evidence suggests broader roles for this protein including glutamate signaling, memory, and regulation of the critical serine/threonine regulatory kinase, glycogen synthase kinase-3 (GSK-3). In this review, genetic and molecular features of FXS are detailed in the context of FXS neuropathology. Additionally, potential mechanisms by which FMRP silencing impacts GSK-3 and GSK-3-associated signaling pathways are discussed. As GSK-3 signaling represents a central regulatory node for critical neurodevelopmental pathways, understanding how FXS results from FMRP-mediated GSK-3 dysregulation may provide novel therapeutic targets for disease-modifying interventions for FXS and related ASDs.
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PMID:The role of glycogen synthase kinase-3 signaling in neurodevelopment and fragile X syndrome. 2307 71

The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) is involved in a broad range of cellular processes including cell proliferation, apoptosis and inflammation. It is now also increasingly acknowledged as having a role to play in cognitive-related processes such as neurogenesis, synaptic plasticity and neural cell survival. Cognitive impairment represents a major debilitating feature of many neurodegenerative and psychiatric disorders, including Alzheimer's disease, mood disorders, schizophrenia and fragile X syndrome, as well as being a result of traumatic brain injury or cranial irradiation. Accordingly, GSK-3 has been identified as an important therapeutic target for cognitive impairment, and recent preclinical studies have yielded important evidence demonstrating that GSK-3 inhibitors may be useful therapeutic interventions for restoring cognitive function in some of these brain disorders. The current review summarises the role of GSK-3 as a regulator of cognitive-dependent functions, examines current preclinical and clinical evidence of the potential of GSK-3 inhibitors as therapeutic agents for cognitive impairments in neuropsychiatric disorders, and offers some insight into the current obstacles that are impeding the clinical use of selective GSK-3 inhibitors in the treatment of cognitive impairment.
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PMID:Glycogen synthase kinase-3 as a therapeutic target for cognitive dysfunction in neuropsychiatric disorders. 2538 Jun 74