Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0344329 (collapse)
 28,634 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neuronal cell death induced by oxidative stress is correlated with numerous neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. The causes of sporadic forms of age-related neurodegenerative diseases are still unknown. Recently, a correlation between paraquat exposure and neurodegenerative diseases has been observed. Paraquat, a nonselective herbicide, was once widely used in North America and is still routinely used in Taiwan. We have used differentiated Human Neuroblastoma (SHSY-5Y) cells as an in vitro model to study the mechanism of cell death induced by paraquat. We observed that paraquat-induced oxidative stress in differentiated SHSY-5Y cells as indicated by an increase in the production of cellular reactive oxygen species (ROS). Furthermore, apoptosis was evident as indicated by cellular and nuclear morphology and DNA fragmentation. Interestingly, pretreatment of SHSY-5Y cells with water-soluble Coenzyme Q10 (CoQ10) before paraquat exposure inhibited ROS generation. Pretreatment with CoQ10 also significantly reduced the number of apoptotic cells and DNA fragmentation. We also analyzed the effect of paraquat and CoQ10 on isolated mitochondria. Our results indicated that treatment with paraquat induced the generation of ROS from isolated mitochondria and depolarization of the inner mitochondrial membrane. Pretreatment with CoQ10 was able to inhibit ROS generation from isolated mitochondria as well as the collapse of mitochondrial membrane potential. Our results indicate that water-soluble CoQ10 can prevent oxidative stress and neuronal damage induced by paraquat and therefore, can be used for the prevention and therapy of neurodegenerative diseases caused by environmental toxins.
 ...
PMID:Paraquat induces oxidative stress and neuronal cell death; neuroprotection by water-soluble Coenzyme Q10. 1551 5

An overload arthrosis occurs consistently in the palmar region of the metacarpal condyle of the equine fetlock (metacarpophalangeal) joint characterized by subchondral bone sclerosis, devitalization and mechanical failure leading to collapse of the overlying articular cartilage. Samples were selected of joints with mild, moderate, and severe subchondral sclerosis, in which cartilage collapse had not yet occurred. An additional group that had severe sclerosis with focal rarefaction suggesting impending collapse was also studied (n=5/group). Parasagittal slices were milled to 2.0 mm thickness and subjected to palmar forces 50 to 200% of those applied by the sesamoid bone at angles corresponding to early, mid and late stance support phases of the gait cycle. From contact radiographs in the loaded and unloaded samples, strains were determined by recognizing displacements in the trabecular patterns using texture correlation analysis. Failure did not occur in any of the samples. Strains were generally proportional to the forces applied and greatest at midstance. Strain patterns varied between samples and with the different loading positions. With increased subchondral bone sclerosis there was greater shear strain in overlying trabeculae. Strain patterns were not consistently different within the sclerotic bone at the site of failure. Focally higher strains at the surface were sometimes related to the edge of the platen which was molded to mimic the sesamoid bone in vivo. These results indicate that sclerotic thickening of subchondral bone transmits stresses to overlying trabeculae. No consistent strain pattern was recognized where devitalization and mechanical failure occurs. Focally higher strains related to the edge of the opposing sesamoid bone may play a role.
J Musculoskelet Neuronal Interact 2001 Jun
PMID:Overload arthrosis: strain patterns in the equine metacarpal condyle. 1575 86

Neuronal development requires highly coordinated regulation of the cytoskeleton within the developing axon. This dynamic regulation manifests itself in axonal branching, turning and pathfinding, presynaptic differentiation, and growth cone collapse and extension. Semaphorin 3A (Sema3A), a secreted guidance cue that primarily functions to repel axons from inappropriate targets, induces cytoskeletal rearrangements that result in growth cone collapse. These effects require intra-axonal messenger RNA translation. Here we show that transcripts for RhoA, a small guanosine triphosphatase (GTPase) that regulates the actin cytoskeleton, are localized to developing axons and growth cones, and this localization is mediated by an axonal targeting element located in the RhoA 3' untranslated region (UTR). Sema3A induces intra-axonal translation of RhoA mRNA, and this local translation of RhoA is necessary and sufficient for Sema3A-mediated growth cone collapse. These studies indicate that local RhoA translation regulates the neuronal cytoskeleton and identify a new mechanism for the regulation of RhoA signalling.
 ...
PMID:Local translation of RhoA regulates growth cone collapse. 1610 49

Neuronal depolarization causes larger intracellular pH (pH(i)) shifts in axonal and dendritic regions than in the cell body. In this paper, we present evidence relating the time for collapse of these gradients to neuronal morphology. We have used ratiometric pH(i) measurements using 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS) in whole-cell patch-clamped snail neurons to study the collapse of longitudinal pH gradients. Using depolarization to open voltage-gated proton channels, we produced alkaline pH(i) microdomains. In the absence of added mobile buffers, facilitated H(+) diffusion down the length of the axon plays a critical role in determining pH(i) microdomain lifetime, with axons of approximately 100 microm allowing pH differences to be maintained for >60 s. An application of mobile, membrane-permeant pH buffers accelerated the collapse of the alkaline-pH gradients but, even at 30 mM, was unable to abolish them. Modeling of the pH(i) dynamics showed that both the relatively weak effect of the weak acid/base on the peak size of the pH gradient and the accelerated collapse of the pH gradient could be due to the time taken for equilibration of the weak acid and base across the cell. We propose that appropriate weak acid/base mixes may provide a simple method for studying the role of local pH(i) signals without perturbing steady-state pH(i). Furthermore, an extrapolation of our in vitro data to longer and thinner neuronal structures found in the mammalian nervous system suggests that dendritic and axonal pH(i) are likely to be dominated by local pH(i)-regulating mechanisms rather than simply following the soma pH(i).
 ...
PMID:The effect of neuronal morphology and membrane-permeant weak acid and base on the dissipation of depolarization-induced pH gradients in snail neurons. 1634 77

Neuronal outgrowth is a fundamental process for normal development of the nervous system. Despite recent advances, the molecular mechanisms governing neuronal motility are still poorly understood. To provide insight into the intracellular signaling mechanisms required for neuronal outgrowth, we have characterized the effects of a compound previously identified for its anti-motility effects on transformed cells. We show that this compound, motuporamine C, acts as a robust inhibitor of chick neurite outgrowth in a dose-dependent fashion. Furthermore, in the presence of motuporamine C, growth cone collapse is observed, followed by neurite retraction. After removal, growth cones re-extend lamellipodial and filopodial processes and re-establish motility. Neurons exposed to motuporamine C exhibit a significant upregulation of active Rho-GTP. Additionally, effector-blocking experiments using Rho and Rho-associated kinase inhibitors indicate that the Rho pathway plays a critical role in motuporamine C-mediated growth cone collapse. Thus, we have characterized a novel anti-motility compound that has a robust inhibitory effect on neuronal outgrowth and involves signaling through the Rho-Rho kinase collapse pathway. Due to these robust effects, motuporamine C may serve as a valuable tool in further examining the intracellular mechanisms associated with growth cone motility.
 ...
PMID:The anti-invasive compound motuporamine C is a robust stimulator of neuronal growth cone collapse. 1656 36

In neurons, the interaction of laminin with its receptor, beta1 integrin, is accompanied by an increase in cytosolic Ca2+. Neuronal behavior is influenced by CaMK-II, the type II Ca2+/calmodulin-dependent protein kinase, which is enriched in axons of mouse embryonic neurons. In this study, we sought to determine whether CaMK-II is activated by laminin, and if so, how CaMK-II influences axonal growth and stability. Axons grew up to 200 microm within 1 day of plating P19 embryoid bodies on laminin-1 (EHS laminin). Activated CaMK-II was found enriched along the axon and in the growth cone as detected using a phospho-Thr(287) specific CaMK-II antibody. beta1 integrin was found in a similar pattern along the axon and in the growth cone. Direct inhibition of CaMK-II in 1-day-old neurons immediately froze growth cone dynamics, disorganized F-actin and ultimately led to axon retraction. Collapsed axonal remnants exhibited diminished phospho-CaMK-II levels. Treatment of 1-day neurons with a beta1 integrin-blocking antibody (CD29) also reduced axon length and phospho-CaMK-II levels and, like CaMK-II inhibitors, decreased CaMK-II activation. Among several CaMK-II variants detected in these cultures, the 52-kDa delta variant preferentially associated with actin and beta 3 tubulin as determined by reciprocal immunoprecipitation. Our findings indicate that persistent activation of delta CaMK-II by laminin stabilizes nascent embryonic axons through its influence on the actin cytoskeleton.
 ...
PMID:Laminin activates CaMK-II to stabilize nascent embryonic axons. 1669 36

Mechanical overload leads to a common arthrosis in the metacarpal condyle of the fetlock joint of racehorses. This is usually asymptomatic but severe forms can cause lameness. Subchondral bone failure is often present and the predictability of the site provided an opportunity to study of the progression of bone failure from microcracks to actual collapse of subchondral bone. Twenty-five fetlock condyles from racehorses with various stages of disease were selected. Stages ranged from mild through severe subchondral bone sclerosis, to the collapse of bone and indentation or loss of cartilage known as 'traumatic osteochondrosis'. Parasagittal slices were radiographed and examined with scanning electron microscopy. Fine matrix cracks were seen in the subchondral bone layer above the calcified cartilage and suggested loss of water or other non-collagenous components. The earliest microcracks appeared to develop in the sclerotic bone within 1-3 mm of the calcified cartilage layer and extend parallel to it in irregular branching lines. Longer cracks or microfractures appeared to develop gaps as fragmentation occurred along the margins. Occasional osteoclastic resorption sites along the fracture lines indicated activated remodeling may have caused previous weakening. In one sample, smoothly ground fragments were found in a fracture gap. Bone collapse occurred when there was compaction of the fragmented matrix along the microfracture. Bone collapse and fracture lines through the calcified cartilage were associated with indentation of articular cartilage at the site.
J Musculoskelet Neuronal Interact
PMID:Subchondral bone failure in overload arthrosis: a scanning electron microscopic study in horses. 1714 46

Frataxin deficiency in Friedreich's ataxia (FRDA) causes cardiac, endocrine, and nervous system manifestations. Frataxin is a mitochondrial protein, and adequate amounts are essential for cellular iron homeostasis. The main histological lesion in the brain of FRDA patients is neuronal atrophy and a peculiar proliferation of synaptic terminals in the dentate nucleus termed grumose degeneration. This cerebellar nucleus may be especially susceptible to FRDA because it contains abundant iron. We examined total iron and selected iron-responsive proteins in the dentate nucleus of nine patients with FRDA and nine normal controls by biochemical and microscopic techniques. Total iron (1.53 +/- 0.53 mumol/g wet weight) and ferritin (206.9 +/- 46.6 mug/g wet weight) in FRDA did not significantly differ from normal controls (iron: 1.78 +/- 0.88 mumol/g; ferritin: 210.9 +/- 9.0 mug/g) but Western blots exhibited a shift to light ferritin subunits. Immunocytochemistry of the dentate nucleus revealed loss of juxtaneuronal ferritin-containing oligodendroglia and prominent ferritin immunoreactivity in microglia and astrocytes. Mitochondrial ferritin was not detectable by immunocytochemistry. Stains for the divalent metal transporter 1 confirmed neuronal loss while endothelial cells reacting with antibodies to transferrin receptor 1 protein showed crowding of blood vessels due to collapse of the normal neuropil. Regions of grumose degeneration were strongly reactive for ferroportin. Purkinje cell bodies, their dendrites and axons, were also ferroportin-positive, and it is likely that grumose degeneration is the morphological manifestation of mitochondrial iron dysmetabolism in the terminals of corticonuclear fibers. Neuronal loss in the dentate nucleus is the likely result of trans-synaptic degeneration.
 ...
PMID:The dentate nucleus in Friedreich's ataxia: the role of iron-responsive proteins. 1744 34

Neuronal migration and growth-cone extension are both guided by extracellular factors in the developing brain, but whether these two forms of guidance are mechanistically linked is unclear. Application of a Slit-2 gradient in front of the leading process of cultured cerebellar granule cells led to the collapse of the growth cone and the reversal of neuronal migration, an event preceded by a propagating Ca(2+) wave from the growth cone to the soma. The Ca(2+) wave was required for the Slit-2 effect and was sufficient by itself to induce the reversal of migration. The Slit-2-induced reversal of migration required active RhoA, which was accumulated at the front of the migrating neuron, and this polarized RhoA distribution was reversed during the migration reversal induced by either the Slit-2 gradient or the Ca(2+) wave. Thus, long-range Ca(2+) signaling coordinates the Slit-2-induced changes in motility at two distant parts of migrating neurons by regulating RhoA distribution.
 ...
PMID:Long-range Ca2+ signaling from growth cone to soma mediates reversal of neuronal migration induced by slit-2. 1744 96

Neuronal Nogo-66 receptor 1 (NgR1) has been proposed to function as an obligatory coreceptor for the myelin-derived ligands Nogo-A, oligodendrocyte myelin glycoprotein (OMgp), and myelin-associated glycoprotein (MAG) to mediate neurite outgrowth inhibition by these ligands. To examine the contribution of neuronal NgR1 to outgrowth inhibition, we used two different strategies, genetic ablation of NgR1 through the germline and transient short hairpin RNA interference (shRNAi)-mediated knock-down. To monitor growth inhibition, two different paradigms were used, chronic presentation of substrate-bound inhibitor to measure neurite extension and acute application of soluble inhibitor to assay growth cone collapse. We find that regardless of the NgR1 genotype, membrane-bound MAG strongly inhibits neurite outgrowth of primary cerebellar, sensory, and cortical neurons. Similarly, substrate-bound OMgp strongly inhibits neurite outgrowth of NgR1 wild-type and mutant sensory neurons. Consistent with these results, shRNAi-mediated knock-down of neuronal NgR1 does not result in a substantial release of L-MAG (large MAG) inhibition. When applied acutely, however, MAG-Fc and OMgp-Fc induce a modest degree of growth cone collapse that is significantly attenuated in NgR1-null neurons compared with wild-type controls. Based on our findings and previous studies with Nogo-66, we propose that neuronal NgR1 has a circumscribed role in regulating cytoskeletal dynamics after acute exposure to soluble MAG, OMgp, or Nogo-66, but is not required for these ligands to mediate their growth-inhibitory properties in chronic outgrowth experiments. Our results thus provide unexpected evidence that the growth cone-collapsing activities and substrate growth-inhibitory activities of inhibitory ligands can be dissociated. We also conclude that chronic axon growth inhibition by myelin is mediated by NgR1-independent mechanisms.
 ...
PMID:The Nogo-66 receptor NgR1 is required only for the acute growth cone-collapsing but not the chronic growth-inhibitory actions of myelin inhibitors. 1795 86


<< Previous 1 2 3 4 Next >>