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)

Neurofilaments are synthesised in neuronal cell bodies and then transported through axons. Damage to neurofilament transport is seen in amyotrophic lateral sclerosis (ALS). Here, we show that PKN1, a neurofilament head-rod domain kinase is cleaved and activated in SOD1G93A transgenic mice that are a model of ALS. Moreover, we demonstrate that glutamate, a proposed toxic mechanism in ALS leads to caspase cleavage and disruption of PKN1 in neurons. Finally, we demonstrate that a cleaved form of PKN1 but not wild-type PKN1 disrupts neurofilament organisation and axonal transport. Thus, deregulation of PKN1 may contribute to the pathogenic process in ALS.
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PMID:Deregulation of PKN1 activity disrupts neurofilament organisation and axonal transport. 1851 42

Kinases, which number > 500 in humans, are a class of enzymes that participate in an array of important functions within normal cellular physiology and during various pathological conditions. Due to the key role of kinases in the regulation of all aspects of cellular signaling and the well established contribution of kinase dysregulation to the etiology of many human pathologies, the development of kinase inhibitors has emerged as a therapeutic strategy for the treatment of human disease, including most notably oncology. Difficulties generating selective inhibitors have hampered their use in other therapeutic areas with less tolerance for off-target effects. However, with an increasing understanding of kinase structures and with the advent of newer inhibitor design strategies more highly selective inhibitors are beginning to emerge. This has prompted interest in utilizing kinase inhibitors in therapeutic areas beyond oncology, including acute and chronic neurodegenerative conditions for which disease modify therapies are lacking. This review provides a background in acute (i.e. brain ischemia and traumatic brain injury) and chronic (i.e. Alzheimer's, Parkinson's, Huntington's disease, amyotrophic lateral sclerosis and multiple sclerosis) neurodegenerative conditions. Then, the role of several kinase (i.e. JNK3, p38 MAPK, ERK, PKC, ROCKII, GSK3, Cdk5, MLK, EphB3 kinase, RIP1 kinase, LRRK2, TTBK1, ASK1, CK, DAPK, and PKN1) that could serve as potential therapeutic targets for these maladies are reviewed.
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PMID:Kinase inhibitors as potential therapeutics for acute and chronic neurodegenerative conditions. 1975 Dec 4

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