Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.4.4 (kinesin)
 5,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To test the hypothesis that fast anterograde molecular motor proteins power the slow axonal transport of neurofilaments (NFs), we used homologous recombination to generate mice lacking the neuronal-specific conventional kinesin heavy chain, KIF5A. Because null KIF5A mutants die immediately after birth, a synapsin-promoted Cre-recombinase transgene was used to direct inactivation of KIF5A in neurons postnatally. Three fourths of such mutant mice exhibited seizures and death at around 3 wk of age; the remaining animals survived to 3 mo or longer. In young mutant animals, fast axonal transport appeared to be intact, but NF-H, as well as NF-M and NF-L, accumulated in the cell bodies of peripheral sensory neurons accompanied by a reduction in sensory axon caliber. Older animals also developed age-dependent sensory neuron degeneration, an accumulation of NF subunits in cell bodies and a reduction in axons, loss of large caliber axons, and hind limb paralysis. These data support the hypothesis that a conventional kinesin plays a role in the microtubule-dependent slow axonal transport of at least one cargo, the NF proteins.
 ...
PMID:Abnormal neurofilament transport caused by targeted disruption of neuronal kinesin heavy chain KIF5A. 1268 84

Cortical malformations are a collection of disorders affecting brain development. Mutations in the LIS1 gene lead to a disorganized and smooth cerebral cortex caused by failure in neuronal migration. Among the clinical consequences of lissencephaly are mental retardation and intractable epilepsy. It remains unclear whether the seizures result from aberrant neuronal placement, disruption of intrinsic properties of neurons, or both. The nematode Caenorhabditis elegans offers an opportunity to study such convulsions in a simple animal with a defined nervous system. Here we show that convulsions mimicking epilepsy can be induced by a mutation in a C. elegans lis-1 allele (pnm-1), in combination with a chemical antagonist of gamma-aminobutyric acid (GABA) neurotransmitter signaling. Identical convulsions were obtained using C. elegans mutants defective in GABA transmission, whereas none of these mutants or the antagonist alone caused convulsions, indicating a threshold was exceeded in response to this combination. Crosses between pnm-1 and fluorescent marker strains designed to exclusively illuminate either the processes of GABAergic neurons or synaptic vesicles surprisingly showed no deviations in neuronal architecture. Instead, presynaptic defects in GABAergic vesicle distribution were clearly evident and could be phenocopied by RNAi directed against cytoplasmic dynein, a known LIS1 interactor. Furthermore, mutations in UNC-104, a neuronal-specific kinesin, and SNB-1, a synaptic vesicle-associated protein termed synaptobrevin, exhibit similar convulsion phenotypes following chemical induction. Taken together, these studies establish C. elegans as a system to investigate subtle cytoskeletal mechanisms regulating intrinsic neuronal activity and suggest that it may be possible to dissociate the epileptic consequences of lissencephaly from the more phenotypically overt cortical defects associated with neuronal migration.
 ...
PMID:Epileptic-like convulsions associated with LIS-1 in the cytoskeletal control of neurotransmitter signaling in Caenorhabditis elegans. 1525 12

Fusion of synaptic vesicles with the plasma membrane is mediated by the SNARE (soluble NSF attachment receptor) proteins and is regulated by synaptotagmin (syt). There are at least 17 syt isoforms that have the potential to act as modulators of membrane fusion events. Synaptotagmin IV (syt IV) is particularly interesting; it is an immediate early gene that is regulated by seizures and certain classes of drugs, and, in humans, syt IV maps to a region of chromosome 18 associated with schizophrenia and bipolar disease. Syt IV has recently been found to localize to dense core vesicles in hippocampal neurons, where it regulates neurotrophin release. Here we have examined the ultrastructure of cultured hippocampal neurons from wild-type and syt IV -/- mice using electron tomography. Perhaps surprisingly, we observed a potential synaptic vesicle transport defect in syt IV -/- neurons, with the accumulation of large numbers of small clear vesicles (putative axonal transport vesicles) near the trans-Golgi network. We also found an interaction between syt IV and KIF1A, a kinesin known to be involved in vesicle trafficking to the synapse. Finally, we found that syt IV -/- synapses exhibited reduced numbers of synaptic vesicles and a twofold reduction in the proportion of docked vesicles compared to wild-type. The proportion of docked vesicles in syt IV -/- boutons was further reduced, 5-fold, following depolarization.
 ...
PMID:Loss of synaptotagmin IV results in a reduction in synaptic vesicles and a distortion of the Golgi structure in cultured hippocampal neurons. 2013 28

Haploinsufficiency is a state of genetic disease, which is caused by hemizygous mutations of functional alleles. Lissencephaly is a typical example of haploinsufficiency disorders characterized by a smooth cerebral surface, thick cortex and dilated lateral ventricules associated with mental retardation and seizures due to defective neuronal migration. LIS1 was the first gene cloned in an organism, which was deleted or mutated in patients with lissencephaly in a heterozygous fashion. Series of studies uncovered that LIS1 is an essential regulator of cytoplasmic dynein. In particular, we reported that LIS1 is essential for dynein transport to the plus-end of microtubules by kinesin, which is essential for maintaining proper distribution of cytoplasmic dynein within the cell. Fortuitously, we found that a substantial fraction of LIS1 is degraded by the cystein protease, calpain after reaching the plus-end of microtubules. We further demonstrated that inhibition of calpain-mediated LIS1 degradation increased LIS1 level at the cortex of the cell, resulting in therapeutic benefit using genetic mouse models with reduced levels of LIS1. Our work might provide a potential therapeutic approach for the treatment of a fraction of haploinsufficiency disorders through augmenting reduced proteins by the targeting inhibition of degradation machinery.
 ...
PMID:A novel strategy for therapeutic intervention for the genetic disease: preventing proteolytic cleavage using small chemical compound. 2054 Oct 31

Heterozygous LIS1 mutations are the most common cause of human lissencephaly, a human neuronal migration defect, and DCX mutations are the most common cause of X-linked lissencephaly. Lissencephaly is characterized by a smooth cerebral surface, thick cortex and dilated lateral ventricles associated with mental retardation and seizures due to defective neuronal migration. Lissencephaly due to the heterozygous loss of the gene LIS1 is a good example of a haploinsufficiency disorder. LIS1 was deleted or mutated in a large proportion of patients with lissencephaly in a heterozygous fashion. A series of studies discovered that LIS1 is an essential regulator of cytoplasmic dynein. Notably, the role of LIS1 in regulating dynein activity is highly conserved among eukaryotes. In particular, we reported that LIS1 and NDEL1 are essential for dynein transport to the plus-end of microtubules by kinesin, which is essential to maintain the proper distribution of cytoplasmic dynein within the cell. In addition, we report that mNUDC (mammalian NUDC) interacts with kinesin-1 and is required for the anterograde transport of a cytoplasmic dynein complex by kinesin-1. A microtubule organization and motor proteins are further modulated by post-translational modifications, including phosphorylation and palmitoylation. These modifications share a common pathway with mitotic cell division. For example, Aurora-A is activated during neurite elongation, and phosphorylates NDEL1, which facilitates microtubule extension into neurite processes. Elucidations of molecular pathways involving neuronal migrations provide us a chance to design a novel strategy for neurological disorder due to defective neuronal migration. For example, inhibition of calpain protects LIS1 from proteolysis resulting in the augmentation of LIS1 levels, which leads to rescue of the phenotypes that are observed in Lis1+/- mice. Endeavoring to address the regulation of the microtubule network and motor proteins will help in understanding not only corticogenesis but neurodegenerative disorders.
 ...
PMID:A unique role of dynein and nud family proteins in corticogenesis. 2239 75

Novel non-blinking quantum dots (NBQDs) were utilized in three-dimensional super-localization, high-precision tracking applications under an automated scanning-angle total internal reflection fluorescence microscope (SA-TIRFM). NBQDs were randomly attached to stationary microtubules along the radial axis under gliding assay conditions. By automatically scanning through a wide range of incident angles with different evanescent-field layer thicknesses, the fluorescence intensity decay curves were obtained. Fit with theoretical decay functions, the absolute vertical positions were determined with sub-10-nm localization precision. The emission intensity profile of the NBQDs attached to kinesin-propelled microtubules was used to resolve the self-rotation of gliding microtubules within a small vertical distance of ~50 nm. We demonstrate the applicability of NBQDs in high-precision fluorescence imaging experiments.
 ...
PMID:High-precision tracking with non-blinking quantum dots resolves nanoscale vertical displacement. 2245 33

The KIF5A gene (OMIM 602821) encodes a neuron-specific kinesin heavy chain involved in intracellular transport of mitochondria and other cargoes. KIF5A protein comprises the N terminal motor domain, the stalk domain and the C-terminal cargo binding domain. The binding between KIF5A and its cargoes is mediated by kinesin adaptor proteins such as TRAK1 and TRAK2. Numerous missense KIF5A mutations in the motor and stalk domains cause spastic paraplegia type 10 (SPG10, OMIM 604187). Conversely, the role of loss-of-function mutations, especially those affecting the cargo binding domain, is unclear. We describe a novel de novo KIF5A p.Ser974fs/c.2921delC mutation found by whole exome sequencing in a patient with a congenital severe disease characterized by myoclonic seizures and progressive leukoencephalopathy. Since this phenotype differs considerably from the KIF5A/SPG10 disease spectrum we propose that the KIF5A p.Ser974fs and possibly other mutations which lead to truncation of the C-terminal tail of the protein cause a novel disorder. We speculate that the unique effect of the C-terminal truncating KIF5A mutations may result from the previously described complex role of this protein domain in binding of the TRAK2 and possibly other kinesin adaptor protein(s).
 ...
PMID:KIF5A de novo mutation associated with myoclonic seizures and neonatal onset progressive leukoencephalopathy. 2741 45