Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mammalian brains are highly compartmentalized into groups of functionally specialized neurons. Cell migration and neurite outgrowth must be tightly orchestrated to achieve this level of organization. A small serine/threonine kinase that shows homology to cyclin-dependent kinases (Cdks) has emerged as an important regulator of neuronal migration. Cdk5, unlike other Cdks, is not regulated by cyclins, and its activity is primarily detected in postmitotic neurons in developing and adult nervous systems. This review describes work indicating that Cdk5 links extracellular signaling pathways and cytoskeletal/membrane systems to direct neuronal migration, axon growth, and possibly neurosecretion. Despite its importance, unchecked Cdk5 activity is toxic to neurons, and may underlie some of the pathologies associated with neurodegenerative disorders such as Alzheimer's disease and amyotrophic lateral sclerosis.
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PMID:Cdk5 on the brain. 1143 2

Cdk5, a serine/threonine kinase in the cyclin-dependent kinase (Cdk) family, is an important regulator of neuronal positioning during brain development. Cdk5 might also play a role in synaptogenesis and neurotransmission. Loss of Cdk5 in mice is perinatal lethal, and overactive Cdk5 induces apoptosis in cultured cells, indicating that strict regulation of kinase activity is crucial. Indeed, activity depends on the stability of activating partners, subcellular localization and the phosphorylation state of the enzyme itself. Deregulated kinase activity has been linked to neurodegenerative diseases such as Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). This review focuses on links between Cdk5 activity and components of cytoskeletal, membrane and adhesion systems that allow us to postulate a role for Cdk5 in directing intracellular traffic in neurons.
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PMID:Cdk5 behind the wheel: a role in trafficking and transport? 1185 7

Cdk5 (cyclin-dependent kinase 5) is a serine/threonine kinase implicated to play pivotal roles in neuronal development. Recently, its potential involvement as a regulator of neuronal death and survival has attracted considerable interests. Importantly, increasing evidence has linked Cdk5 to the etiopathology of neurodegenerative diseases such as Alzheimer's disease and amyotrophic lateral sclerosis. Here we summarize the recent findings on Cdk5 not only as an important participant in neuronal death, but also a key player in neuronal survival. Elucidating the mechanisms of regulation of Cdk5 and its downstream signaling might prove to be crucial in the therapeutic treatment of neurodegenerative diseases.
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PMID:Cdk5: mediator of neuronal death and survival. 1513 90

Cyclin-dependent kinase 5 (CDK5) is a serine/threonine kinase that plays a critical role in the early development of the nervous system. Deregulation of CDK5 is believed to contribute to the abnormal phosphorylation of various cellular substrates associated with neurodegenerative disorders such as Alzheimer's disease, amyotrophic lateral sclerosis, and ischemic stroke. Acyclic urea 3 was identified as a potent CDK5 inhibitor and co-crystallographic data of urea 3/CDK2 enzyme were used to design a novel series of 3,4-dihydroquinazolin-2(1H)-ones as CDK5 inhibitors. In this investigation we present our synthetic studies toward this series of compounds and discuss their biological relevance as CDK5 inhibitors.
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PMID:Structure-activity relationships of 3,4-dihydro-1H-quinazolin-2-one derivatives as potential CDK5 inhibitors. 1769 81

Cyclin-dependent kinase 5 (Cdk5) is a proline-directed serine/threonine kinase, and plays multiple roles in neuron development and synaptic plasticity. The active form of Cdk5 is found primarily in the central nervous system (CNS) due to its activator proteins p35 or p39 ubiquitously expressed in neuronal cells. Normally, the transcription and activity of Cdk5 are strictly regulated by several ways. In the physiological condition, Cdk5 plays a key role in the CNS development by phosphorylating the specific serine or threonine site of numerous substrate proteins that are closely associated with the neuronal migration, synaptogenesis, synaptic transmission as well as synaptic plasticity. Under pathological conditions, p35 can be truncated into p25, which can strongly and consistently activate Cdk5, change the cellular localization of Cdk5 and lead to neuronal death ultimately. The increasing evidence has showed that Cdk5 is involved in the pathogenesis of many neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis etc., indicating that Cdk5 may be a potential target in the treatment of the neurodegenerative diseases. In this article, we reviewed the recent progress regarding the roles of Cdk5 in CNS development and neurodegenerative diseases.
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PMID:[Roles of cyclin-dependent kinase 5 in central nervous system development and neurodegenerative diseases]. 2071 30

Cyclin-dependent kinase 5 (Cdk5) is a peculiar proline-directed serine/threonine kinase. Unlike the other members of the Cdk family, Cdk5 is not directly involved in cell cycle regulation, being normally associated with neuronal processes such as migration, cortical layering and synaptic plasticity. This kinase is present mainly in post-mitotic neurons and its activity is tightly regulated by the interaction with the specific activators, p35 and p39. Despite its pivotal role in CNS development, Cdk5 dysregulation has been implicated in different pathologies, such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD) and, most recently, prion-related encephalopathies (PRE). In these neurodegenerative conditions, Cdk5 overactivation and relocalization occurs upon association with p25, a truncated form of the normal activator p35. This activator switching will cause a shift in the phosphorylative pattern of Cdk5, with an alteration both in targets and activity, ultimately leading to neuronal demise. In AD and PRE, two disorders that share clinical and neuropathological features, Cdk5 dysregulation is a linking event between the major neuropathological markers: amyloid plaques, tau hyperphosphorylation and synaptic and neuronal loss. Moreover, this kinase was shown to be involved in abortive cell cycle re-entry, a feature recently proposed as a possible step in the neuronal apoptosis mechanism of several neurological diseases. This review focuses on the role of Cdk5 in neurons, namely in the regulation of cytoskeletal dynamics, synaptic function and cell survival, both in physiological and in pathological conditions, highlighting the relevance of Cdk5 in the main mechanisms of neurodegeneration in Alzheimer's disease and other brain pathologies.
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PMID:Cdk5: multitasking between physiological and pathological conditions. 2147 99

Cyclin-dependent kinase 5 (Cdk5) is a multifaceted serine/threonine kinase protein with important roles in the nervous system. Two related proteins, p35 and p39, activate Cdk5 upon direct binding. Over the past decade, Cdk5 activity has been demonstrated to regulate many events during brain development, including neuronal migration as well as axon and dendrite development. Recent evidence also suggests a pivotal role for Cdk5 in synaptic plasticity, behavior, and cognition. Dysfunction of Cdk5 has been implicated in a number of neurological disorders and neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Niemann-Pick type C disease, and ischemia. Hyperactivation of Cdk5 due to the conversion of p35 to p25 by the calcium-dependent protease calpain during neurotoxicity also contributes to the pathological state. This review surveys recent literature surrounding Cdk5 in synaptic plasticity and homeostasis, with particular emphasis on Cdk5 kinase activity under neurodegenerative conditions.
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PMID:Cyclin-dependent kinases in brain development and disease. 2174 Feb 29

Serine/threonine protein kinase C-related kinase (PKN/PRK) is a family of three isoenzymes (PKN1, PKN2, PKN3), which are widely distributed in eukaryotic organisms and share the same overall domain structure. The Nterminal region encompasses a conserved repeated domain, termed HR1a-c as well as a HR2/C2 domain. The serine/threonine kinase domain is found in the C-terminal region of the protein and shows high sequence homology to other members of the PKC superfamily. In neurons, PKN1 is the most abundant isoform and has been implicated in a variety of functions including cytoskeletal organization and neuronal differentiation and its deregulation may contribute to neuropathological processes such as amyotrophic lateral sclerosis and Alzheimer's disease. We have recently identified a candidate role of PKN1 in the regulation of neuroprotective processes during hypoxic stress. Our key findings were that: 1) the activity of PKN1 was significantly increased by hypoxia (1% O2) and neurotrophins (nerve growth factor and purine nucleosides); 2) Neuronal cells, deficient of PKN1 showed a decrease of cell viability and neurite formation along with a disturbance of the F-actinassociated cytoskeleton; 3) Purine nucleoside-mediated neuroprotection during hypoxia was severely hampered in PKN1 deficient neuronal cells, altogether suggesting a potentially critical role of PKN1 in neuroprotective processes. This review gives an up-to-date overview of the PKN family with a special focus on the neuroprotective role of PKN1 in hypoxia.
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PMID:Protein Kinase C-Related Kinase (PKN/PRK). Potential Key-Role for PKN1 in Protection of Hypoxic Neurons. 2485 Oct 86

The AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a key energy sensor in a wide variety of tissues. This kinase has been a major drug target for metabolic diseases (e.g., type 2 diabetes) and cancers. For example, metformin (an activator of AMPK) is a first-line diabetes drug that protects against cancers. Abnormal regulation of AMPK has been implicated in several brain diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and stroke. Given the emerging importance of neurodegenerative diseases in our aging societies, this review features the recent studies that have delineated the functions of AMPK in brain diseases and discusses their potential clinical implications or roles as drug targets in brain diseases.
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PMID:AMPK-mediated regulation of neuronal metabolism and function in brain diseases. 2611 1

Cyclin-dependent kinase 5 (CDK5) is a proline-directed serine/threonine kinase belonging to the family of cyclin-dependent kinases. In addition to maintaining the neuronal architecture, CDK5 plays an important role in the regulation of synaptic plasticity, neurotransmitter release, neuron migration and neurite outgrowth. Although various reports have shown links between neurodegeneration and deregulation of cyclin-dependent kinases, the specific role of CDK5 inhibition in causing neuroprotection in cases of neuronal insult or in neurodegenerative diseases is not wellunderstood. This article discusses current evidence for the involvement of CDK5 deregulation in neurodegenerative disorders and neurodegeneration associated with stroke through various mechanisms. These include upregulation of cyclin D1 and overactivation of CDK5 mediated neuronal cell death pathways, aberrant hyperphosphorylation of human tau proteins and/or neurofilament proteins, formation of neurofibrillary lesions, excitotoxicity, cytoskeletal disruption, motor neuron death (due to abnormally high levels of CDK5/p25) and colchicine- induced apoptosis in cerebellar granule neurons. A better understanding of the role of CDK5 inhibition in neuroprotective mechanisms will help scientists and researchers to develop selective, safe and efficacious pharmacological inhibitors of CDK5 for therapeutic use against human neurodegenerative disorders, such as Alzheimer's disease, amyotrophic lateral sclerosis and neuronal loss associated with stroke.
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PMID:Neuroprotective Mechanisms Mediated by CDK5 Inhibition. 2660 62


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