Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.6.4.4 (kinesin)
5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The products of the Herpes simplex (HSV-1) genome interact with many Alzheimer's disease susceptibility genes or proteins. These in turn affect those of the virus. For example, HSV-1 binds to heparan sulphate proteoglycans (HSPG2), or alpha-2-macroglobulin (A2M), and enters cells via nectin receptors, which are cleaved by gamma-secretase (APH1B, PSEN1, PSEN2, PEN2, NCSTN). The virus also binds to blood-borne lipoproteins and apolipoprotein E (APOE) is able to modify its infectivity. Viral uptake is cholesterol- and lipid raft-dependent (DHCR24, HMGCR, FDPS, RAFTLIN, SREBF1). The virus is transported to the nucleus via the dynein and kinesin (KNS2) motors associated with the microtubule network (MAPT). Amyloid precursor protein (APP) plays a role in this transport. Nuclear export is mediated via disruption of the nuclear lamina and binding to LMNA. Herpes simplex activates kinases (CDC2 and casein kinase 2) whose substrates include APOE, APP, MAPT, PSEN2, and SREBF1. A viral protein is also able to delete mitochondrial DNA, a situation prevalent in Alzheimer's disease. The virus binds to the host transcription factors transcription factor CP2 (TFCP2) and POU2F1 that control many other genes associated with Alzheimer's disease. Viral latency is controlled by IL6 and IL1B and at different stages of its life cycle the virus can either promote or attenuate apoptosis via Fas and tumor necrosis factor pathways (FAS, TNF, DAPK1, PARP1). Viral evasion strategies include inhibition of the antigen processor TAP2, the production of an Fc immunoglobulin receptor mimic (FCER1G) and inhibition of the viral-activated kinase EIF2AK2. These and other host/viral interactions, targeted to certain Alzheimer's disease susceptibility genes, support the idea that some form of synergy between the pathogen and genetic factors may play a role in the pathology of late-onset Alzheimer's disease.
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PMID:Interactions between the products of the Herpes simplex genome and Alzheimer's disease susceptibility genes: relevance to pathological-signalling cascades. 1816 3

Defective axonal transport has been proposed as an underlying mechanism that may give rise to neurodegeneration. We investigated the effect of phosphorylation on the axonal transport of tau, a neuronal protein that stabilizes microtubules and is hyperphosphorylated and mislocalized in Alzheimer's disease. We report here that specific inhibition of glycogen synthase kinase-3 (GSK-3) reduces tau phosphorylation and significantly decreases the overall rate of axonal transport of tau in rat cortical neurons. Tau mutants, with serine/threonine targets of GSK-3 mutated to glutamate to mimic a permanent state of phosphorylation, were transported at a significantly increased rate compared to wild-type tau. Conversely, tau mutants, in which alanine replaced serine/threonine to mimic permanent dephosphorylation, were transported at a decreased rate compared to wild-type tau. We also found that tau interacts with the light chain of kinesin-1 and that this is dependent on the phosphorylation state of tau. Tau phosphorylation by GSK-3 increased binding, and dephosphorylated tau exhibited a reduced association with kinesin-1. We conclude that GSK-3 phosphorylation of tau modulates its axonal transport by regulating binding to kinesin-1. Hyperphosphorylated tau in Alzheimer's disease appearing first in distal portions of axons may result from aberrant axonal transport of phosphorylated tau reported here.
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PMID:Phosphorylation of tau regulates its axonal transport by controlling its binding to kinesin. 1851 49

We investigated the effects of acetyl-l-carnitine on gene expression by means of the suppression subtractive hybridization method. The approach gives the generation of subtracted cDNA libraries and the subsequent identification of differentially expressed transcripts after treatment of rats with acetyl-l-carnitine for 21 days. We observed that acetyl-l-carnitine increases the light-chain subunit of kinesin-1 gene expression. Recent evidences reported a link between kinesin-1 light-chain and Alzheimer's disease. Pathological hallmarks of Alzheimer's disease are potentially linked to alterations of the axonal compartments. Amyloid-beta peptide is a principal component of senile plaques and is considered to be central in the pathogenesis of the disease. The fast anterograde axonal transport of amyloid-beta peptide is mediated by direct binding to the light-chain subunit of kinesin-1. In this scenario, our results are of relevant importance for possible therapeutic intervention, suggesting a pathway for the treatment of Alzheimer's disease.
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PMID:Up-regulation of kinesin light-chain 1 gene expression by acetyl-L-carnitine: therapeutic possibility in Alzheimer's disease. 1876 85

The neuropathology of Alzheimer's disease (AD) and other tauopathies is characterized by filamentous deposits of the microtubule-associated protein tau, but the relationship between tau polymerization and neurotoxicity is unknown. Here, we examined effects of filamentous tau on fast axonal transport (FAT) using isolated squid axoplasm. Monomeric and filamentous forms of recombinant human tau were perfused in axoplasm, and their effects on kinesin- and dynein-dependent FAT rates were evaluated by video microscopy. Although perfusion of monomeric tau at physiological concentrations showed no effect, tau filaments at the same concentrations selectively inhibited anterograde (kinesin-dependent) FAT, triggering the release of conventional kinesin from axoplasmic vesicles. Pharmacological experiments indicated that the effect of tau filaments on FAT is mediated by protein phosphatase 1 (PP1) and glycogen synthase kinase-3 (GSK-3) activities. Moreover, deletion analysis suggested that these effects depend on a conserved 18-amino-acid sequence at the amino terminus of tau. Interestingly, monomeric tau isoforms lacking the C-terminal half of the molecule (including the microtubule binding region) recapitulated the effects of full-length filamentous tau. Our results suggest that pathological tau aggregation contributes to neurodegeneration by altering a regulatory pathway for FAT.
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PMID:The amino terminus of tau inhibits kinesin-dependent axonal transport: implications for filament toxicity. 1879 83

The amyloid-beta (Abeta) precursor protein (APP), a transmembrane protein that undergoes proteolytic cleavage into defined fragments, has been implicated in axonal transport. The proposed role of APP as a vesicle receptor for the microtubule motor kinesin-1 has relevance for the pathogenesis of Alzheimer's disease. Nevertheless, this function, which relies on the transport to the cell periphery of full-length APP rather than its cleavage fragments, remains controversial. Other proposed functions of APP, such as regulating transcription, neurogenesis, cell movement, or neurite growth also rely on APP's presence as a full-length protein at the cell surface, implying that APP cleavage occurs after its transport to the cell periphery. To test this hypothesis, we mapped the localization of various APP epitopes in neurons in culture and in the mouse brain. Surprisingly, epitopes from the N-terminal, C-terminal, and central (Abeta) domains of APP each showed a distinct distribution throughout the cell and rarely colocalized. Within neurites, these epitopes were localized to distinct transport vesicles that associated with different sets of microtubules and, occasionally, actin filaments. C-terminal APP fragments were preferentially transported into neurites as phosphorylated forms, entered the lamellipodium and filopodia of growth cones, and concentrated in regions of growth cone turning and advancement (unlike the N-terminal and Abeta fragments). We conclude that, under normal conditions, the proteolytic cleavage of APP primarily occurs before its sorting into axonal transport vesicles and the cleaved fragments segregate into separate vesicle populations that reach different destinations, and thus have different functions.
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PMID:The cleavage products of amyloid-beta precursor protein are sorted to distinct carrier vesicles that are independently transported within neurites. 1929 61

The pathological mechanism by which Abeta causes neuronal dysfunction and death remains largely unknown. Deficiencies in fast axonal transport (FAT) were suggested to play a crucial role in neuronal dysfunction and loss for a diverse set of dying back neuropathologies including Alzheimer's disease (AD), but the molecular basis for pathological changes in FAT were undetermined. Recent findings indicate that soluble intracellular oligomeric Abeta (oAbeta) species may play a critical role in AD pathology. Real-time analysis of vesicle mobility in isolated axoplasms perfused with oAbeta showed bidirectional axonal transport inhibition as a consequence of endogenous casein kinase 2 (CK2) activation. Conversely, neither unaggregated amyloid beta nor fibrillar amyloid beta affected FAT. Inhibition of FAT by oAbeta was prevented by two specific pharmacological inhibitors of CK2, as well as by competition with a CK2 substrate peptide. Furthermore, perfusion of axoplasms with active CK2 mimics the inhibitory effects of oAbeta on FAT. Both oAbeta and CK2 treatment of axoplasm led to increased phosphorylation of kinesin-1 light chains and subsequent release of kinesin from its cargoes. Therefore pharmacological modulation of CK2 activity may represent a promising target for therapeutic intervention in AD.
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PMID:Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta. 1932 17

Many neurodegenerative diseases exhibit axonal pathology, transport defects, and aberrant phosphorylation and aggregation of the microtubule binding protein tau. While mutant tau protein in frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP17) causes aberrant microtubule binding and assembly of tau into filaments, the pathways leading to tau-mediated neurotoxicity in Alzheimer's disease and other neurodegenerative disorders in which tau protein is not genetically modified remain unknown. To test the hypothesis that axonal transport defects alone can cause pathological abnormalities in tau protein and neurodegeneration in the absence of mutant tau or amyloid beta deposits, we induced transport defects by deletion of the kinesin light chain 1 (KLC1) subunit of the anterograde motor kinesin-1. We found that upon aging, early selective axonal transport defects in mice lacking the KLC1 protein (KLC1-/-) led to axonopathies with cytoskeletal disorganization and abnormal cargo accumulation. In addition, increased c-jun N-terminal stress kinase activation colocalized with aberrant tau in dystrophic axons. Surprisingly, swollen dystrophic axons exhibited abnormal tau hyperphosphorylation and accumulation. Thus, directly interfering with axonal transport is sufficient to activate stress kinase pathways initiating a biochemical cascade that drives normal tau protein into a pathological state found in a variety of neurodegenerative disorders including Alzheimer's disease.
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PMID:Axonal stress kinase activation and tau misbehavior induced by kinesin-1 transport defects. 1942 Feb 44

In Alzheimer disease (AD) and frontotemporal dementia the microtubule-associated protein Tau becomes progressively hyperphosphorylated, eventually forming aggregates. However, how Tau dysfunction is associated with functional impairment is only partly understood, especially at early stages when Tau is mislocalized but has not yet formed aggregates. Impaired axonal transport has been proposed as a potential pathomechanism, based on cellular Tau models and Tau transgenic mice. We recently reported K369I mutant Tau transgenic K3 mice with axonal transport defects that suggested a cargo-selective impairment of kinesin-driven anterograde transport by Tau. Here, we show that kinesin motor complex formation is disturbed in the K3 mice. We show that under pathological conditions hyperphosphorylated Tau interacts with c-Jun N-terminal kinase- interacting protein 1 (JIP1), which is associated with the kinesin motor protein complex. As a result, transport of JIP1 into the axon is impaired, causing JIP1 to accumulate in the cell body. Because we found trapping of JIP1 and a pathological Tau/JIP1 interaction also in AD brain, this may have pathomechanistic implications in diseases with a Tau pathology. This is supported by JIP1 sequestration in the cell body of Tau-transfected primary neuronal cultures. The pathological Tau/JIP1 interaction requires phosphorylation of Tau, and Tau competes with the physiological binding of JIP1 to kinesin light chain. Because JIP1 is involved in regulating cargo binding to kinesin motors, our findings may, at least in part, explain how hyperphosphorylated Tau mediates impaired axonal transport in AD and frontotemporal dementia.
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PMID:Phosphorylated Tau interacts with c-Jun N-terminal kinase-interacting protein 1 (JIP1) in Alzheimer disease. 1949 Nov 4

Amyloid-beta protein precursor (AbetaPP) is a receptor-like, type-I membrane protein that plays a central role in the pathogenesis of Alzheimer's disease. The cytoplasmic domain of AbetaPP is important for the metabolism and physiological functions of AbetaPP and contains a GYENPTY motif that interacts with proteins that contain a phosphotyrosine binding (PTB) domain such as X11/Mint, FE65, and the JIP family of proteins. X11 and X11-like proteins are neuronal adaptor proteins involved in presynaptic function and the intracellular trafficking of proteins. Recent studies in X11s knockout mice confirmed findings from in vitro studies that X11 proteins affect AbetaPP metabolism and the generation of amyloid-beta peptide. FE65 proteins are involved in transactivation in coordination with the intracellular domain fragment of AbetaPP, and/or in cellular responses to DNA damage. Neurodevelopmental defects observed in FE65s double knockout mice suggest that FE65 proteins cooperate with AbetaPP to play a role in neuronal cytoskeletal regulation. c-Jun N-terminal kinase (JNK) interacting protein-1 (JIP-1), a scaffolding protein for the JNK kinase cascade, has been suggested to mediate the intracellular trafficking of AbetaPP by molecular motor kinesin-1. This article reviews some of the recent findings regarding the regulation of physiological function and metabolism of AbetaPP by AbetaPP binding proteins.
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PMID:Regulation of the physiological function and metabolism of AbetaPP by AbetaPP binding proteins. 1958 34

Alcadeins (Alcs) constitute a family of neuronal type I membrane proteins, designated Alc(alpha), Alc(beta), and Alc(gamma). The Alcs express in neurons dominantly and largely colocalize with the Alzheimer amyloid precursor protein (APP) in the brain. Alcs and APP show an identical function as a cargo receptor of kinesin-1. Moreover, proteolytic processing of Alc proteins appears highly similar to that of APP. We found that APP alpha-secretases ADAM 10 and ADAM 17 primarily cleave Alc proteins and trigger the subsequent secondary intramembranous cleavage of Alc C-terminal fragments by a presenilin-dependent gamma-secretase complex, thereby generating "APP p3-like" and non-aggregative Alc peptides (p3-Alcs). We determined the complete amino acid sequence of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma), whose major species comprise 35, 37, and 31 amino acids, respectively, in human cerebrospinal fluid. We demonstrate here that variant p3-Alc C termini are modulated by FAD-linked presenilin 1 mutations increasing minor beta-amyloid species Abeta42, and these mutations alter the level of minor p3-Alc species. However, the magnitudes of C-terminal alteration of p3-Alc(alpha), p3-Alc(beta), and p3-Alc(gamma) were not equivalent, suggesting that one type of gamma-secretase dysfunction does not appear in the phenotype equivalently in the cleavage of type I membrane proteins. Because these C-terminal alterations are detectable in human cerebrospinal fluid, the use of a substrate panel, including Alcs and APP, may be effective to detect gamma-secretase dysfunction in the prepathogenic state of Alzheimer disease subjects.
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PMID:Alcadein cleavages by amyloid beta-precursor protein (APP) alpha- and gamma-secretases generate small peptides, p3-Alcs, indicating Alzheimer disease-related gamma-secretase dysfunction. 1986 13


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