Abstract:
:Niemann-Pick type C disease (NPCD) was first described in 1914 and affects approximately 1 in 150 000 live births. It is characterized clinically by diverse symptoms affecting liver, spleen, motor control, and brain; premature death invariably results. Its molecular origins were traced, as late as 1997, to a protein of late endosomes and lysosomes which was named NPC1. Mutation or absence of this protein leads to accumulation of cholesterol in these organelles. In this review, we focus on the intracellular events that drive the pathology of this disease. We first introduce endocytosis, a much-studied area of dysfunction in NPCD cells, and survey the various ways in which this process malfunctions. We briefly consider autophagy before attempting to map the more complex pathways by which lysosomal cholesterol storage leads to protein misregulation, mitochondrial dysfunction, and cell death. We then briefly introduce the metabolic pathways of sphingolipids (as these emerge as key species for treatment) and critically examine the various treatment approaches that have been attempted to date.
journal_name
J Neurochemjournal_title
Journal of neurochemistryauthors
Wheeler S,Sillence DJdoi
10.1111/jnc.14895subject
Has Abstractpub_date
2020-06-01 00:00:00pages
674-692issue
6eissn
0022-3042issn
1471-4159journal_volume
153pub_type
杂志文章,评审abstract::Intracerebral administration of [3H]arachidonic acid ([3H]ArA) into 19-20-day-old rat embryos, resulted in a rapid incorporation of label into brain lipids. One hour after injection, 55.6 +/- 8.2, 18.0 +/- 3.4, and 13.7 +/- 1.3% of the total radioactivity was associated with phosphatidylcholine, phosphatidylinositol, ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1992.tb11014.x
更新日期:1992-11-01 00:00:00
abstract::To study potential biochemical correlates of dopamine (DA) and serotonin receptor supersensitivity, rats were lesioned at 3 days after birth with 6-hydroxydopamine (6-OHDA; 67 micrograms in each lateral ventricle; desipramine pretreatment, 20 mg/kg i.p., 1 h) and then sensitized with the DA D1 agonist, SKF 38393 HCl (...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1994.63041282.x
更新日期:1994-10-01 00:00:00
abstract::Bone fracture at the acute stage of stroke exacerbates stroke injury by increasing neuroinflammation. We hypothesize that activation of α-7 nicotinic acetylcholine receptor (α-7 nAchR) attenuates neuroinflammation and oxidative stress, and reduces brain injury in mice with bone fracture and stroke. Permanent middle ce...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.12817
更新日期:2014-11-01 00:00:00
abstract::Most physiological processes in mammals are synchronized to the daily light:dark cycle by a circadian clock located in the hypothalamic suprachiasmatic nucleus. Signal transduction of light-induced phase advances of the clock is mediated through a neuronal nitric oxide synthase-guanilyl cyclase pathway. We have employ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.12613
更新日期:2014-04-01 00:00:00
abstract::Rarefaction of the dendritic tree leading to neuronal dysfunction is a hallmark of many neurodegenerative diseases and we have shown previously that heat shock protein B5 (HspB5)/αB-crystallin is able to increase dendritic complexity in vitro. The aim of this study was to investigate if this effect is also present in ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.15247
更新日期:2020-11-21 00:00:00
abstract::The lipid compositions of 10 different brain regions from patients affected by Alzheimer's disease/senile dementia of Alzheimer's type were analyzed. The total phospholipid amount decreased somewhat in nucleus caudatus and in white matter. The cortical areas that are morphologically affected by Alzheimer's disease, i....
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1992.tb10994.x
更新日期:1992-11-01 00:00:00
abstract::The ability of cholinergic vesicles to incorporate acetylcholine (ACh) was studied using highly purified synaptic vesicles from Torpedo electric organ. Depleted vesicles were capable of rapidly taking up exogenous ACh. Evidence that this represented true incorporation was that labelled ACh comigrated with vesicular AT...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1981.tb00479.x
更新日期:1981-08-01 00:00:00
abstract::gamma-Aminobutyric acid (GABA) and glutamic acid decarboxylase (GAD) activities were measured in the ovary and the Fallopian tube of rats and compared with brain values. GABA levels in the Fallopian tube were about twice as high as in the brain, while in the ovary they represented only about 5% of the amino acid conte...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1984.tb06686.x
更新日期:1984-07-01 00:00:00
abstract::In the present study, by means of genetic, biochemical, morphological, and electrophysiological approaches, the role of large-conductance voltage- and Ca(2+)-dependent K(+) channels (BK channels) in the release of excitatory and non-excitatory neurotransmitters at hippocampal and non-hippocampal sites has been investi...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2010.06938.x
更新日期:2010-10-01 00:00:00
abstract::In the central nervous system, astrocytes extend endfoot processes to ensheath synapses and microvessels. However, the mechanisms underlying this astrocytic process extension remain unclear. A limitation of the use of 2D cultured astrocytes for such studies is that they display a flat, epithelioid morphology, with no ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.14548
更新日期:2018-11-01 00:00:00
abstract::Although it is well established that RhoA signaling pathways play key roles in regulating neuronal morphology, their involvement in other aspects of neuronal function has received little attention. Recent studies have elucidated a novel intracellular signaling pathway used by RhoA to elicit activation of serum respons...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2005.03179.x
更新日期:2005-07-01 00:00:00
abstract::Although alterations in mitochondrial dynamics are associated with cellular responses to injury, the functional role of these dynamic changes in ischemic neurons is underexplored. One of these dynamic responses to injury includes mitochondrial biogenesis. Various sublethal pre-conditioning stimuli that induce an ische...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2012.07951.x
更新日期:2012-11-01 00:00:00
abstract::Glycine residues can introduce flexibility in proteins, give rise to turns and breaks in secondary structure and are key components of some nucleotide binding motifs. In the P2X receptor extracellular ATP binding domain, 11 glycine residues are completely conserved and an additional five are conserved in at least five...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2005.03494.x
更新日期:2005-12-01 00:00:00
abstract::The objective of the present study was to explore mechanisms responsible for activation of ion conductances in the initial phases of brain ischemia, particularly for the early release of K+ that precedes massive cell depolarization, and rapid downhill fluxes of K+, Na+, Cl-, and Ca2+. As it has been speculated that a ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1990.tb04957.x
更新日期:1990-11-01 00:00:00
abstract::The aim of this study is to examine how sustained exposure to two 1,4-benzodiazepines (BZDs) with different action period, diazepam and brotizolam, and a 1,5-BZD, clobazam, affects L-type high voltage-gated calcium channel (HVCC) functions and its mechanisms using primary cultures of mouse cerebral cortical neurons. T...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2007.04984.x
更新日期:2007-12-01 00:00:00
abstract::Type 1 cannabinoid receptor (CB1) is expressed in different neuronal populations in the mammalian brain. In particular, CB1 on GABAergic or glutamatergic neurons exerts different functions and display different pharmacological properties in vivo. This suggests the existence of neuron-type specific signalling pathways ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.12137
更新日期:2013-03-01 00:00:00
abstract::Activation of the apoptogenic sphingomyelin-dependent signaling pathway in neuronally differentiated PC12 cells with cell-permeant C2-ceramide resulted in a transient and short-lived emission of reactive oxygen species that was maximal 6 h after the beginning of treatment, followed immediately by nuclear translocation...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1997.69041612.x
更新日期:1997-10-01 00:00:00
abstract::Alzheimer's disease (AD) is a neurodegenerative disorder in which oxidative stress has been implicated as an important event in the progression of the pathology. In particular, it has been shown that protein modification by reactive oxygen species (ROS) occurs to a greater extent in AD than in control brain, suggestin...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2002.01103.x
更新日期:2002-09-01 00:00:00
abstract::We have recently shown that disrupting the expression and post-synaptic clustering of gephyrin in cultured hippocampal pyramidal cells, by either gephyrin RNAi (RNA interference) or over-expression of a dominant negative gephyrin-enhanced green fluorescent protein (EGFP) fusion protein, leads to decreased number of po...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2007.05014.x
更新日期:2008-02-01 00:00:00
abstract::We found in cultured glioma (C6BU-1) cells that excitatory amino acids (EAAs) such as glutamate, N-methyl-D-aspartate (NMDA), aspartate, and metabotropic glutamate receptor agonist trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylate caused an increase in the inositol 1,4,5-trisphosphate formation and the intracellular C...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1994.63041346.x
更新日期:1994-10-01 00:00:00
abstract::The FE65 adaptor protein family was identified in two-hybrid screens as proteins that bind the cytoplasmic domain of the amyloid precursor protein (APP). Studies have shown that FE65 binding to APP modulates APP processing. Increased levels of alpha-secretase derived secreted APP (APPsalpha) and beta-amyloid (Abeta) w...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.2002.01009.x
更新日期:2002-08-01 00:00:00
abstract::Neuronal nicotinic acetylcholine receptors labelled with tritiated agonists are reduced in the cerebral cortex in Alzheimer's disease (AD), but to date it has not been demonstrated which nicotinic receptor subunits contribute to this deficit. In the present study, autopsy tissue from the temporal cortex of 14 AD cases...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1999.0731635.x
更新日期:1999-10-01 00:00:00
abstract::High-affinity binding sites for [3H]PK 11195 and [3H]Ro 5-4864 with the properties of the peripheral-type benzodiazepine receptor were detected in primary cultures of both mouse neocortical and cerebellar astrocytes. The binding sites were enriched in mitochondrial fractions on differential centrifugation. An 18-kDa p...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1994.62020673.x
更新日期:1994-02-01 00:00:00
abstract::The autoradiographic method with L-[35S]methionine was used to determine the effects of an n-3 fatty acid deficiency on brain protein synthesis. Brain protein synthesis was significantly increased (from 50 to 150%) in 45 of the 52 brain structures studied in n-3 fatty acid-deficient rats as compared with control anima...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1994.63051995.x
更新日期:1994-11-01 00:00:00
abstract::Retinal ganglion cells transmit the visual signal from the retina to the brain. We have previously shown that the activator protein 2 (AP-2)δ (TFAP2D) transcription factor is expressed in one third of ganglion cells in developing retina suggesting a specialized role for these AP-2δ-expressing cells. Here, we address t...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/jnc.12521
更新日期:2014-04-01 00:00:00
abstract::Neuronal nitric oxide synthase (nNOS) is a component of the dystrophin complex in skeletal muscle. The absence of dystrophin protein in Duchenne muscular dystrophy and in mdx mouse causes a redistribution of nNOS from the plasma membrane to the cytosol in muscle cells. Aberrant nNOS activity in the cytosol can induce ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1998.71020784.x
更新日期:1998-08-01 00:00:00
abstract::The beta-amyloid peptide (Abeta) is considered responsible for the pathogenesis of Alzheimer's disease. Despite the magnitude of reports describing a neurotoxic role of extracellular Abeta, the role for intracellular Abeta (iAbeta) has not been elucidated. We previously demonstrated that in rat pheochromocytoma cells ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2007.04704.x
更新日期:2007-10-01 00:00:00
abstract::Quantitative proton and quantitative proton-decoupled 31P magnetic resonance spectroscopy (MRS) of the brain was performed in 16 patients with liver disease (10 with and six without chronic hepatic encephalopathy) and four patients with hyponatremia, as well as 20 age-matched normal subjects. Patients with hepatic enc...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1046/j.1471-4159.1998.71041564.x
更新日期:1998-10-01 00:00:00
abstract::In a study employing mouse brain synaptosomes and synaptosomal sonicates, the complete metabolic machinery was found to be present for transport of arginine into synaptosomes, its conversion to ornithine, and the formation from the latter of glutamic acid, gamma-aminobutyric acid, and proline. The results show that a ...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.1984.tb12719.x
更新日期:1984-04-01 00:00:00
abstract::The group I metabotropic glutamate receptor agonist (S)-3,5-dihydroxyphenylglycine (DHPG) elicited two phases of synchronized neuronal (epileptiform) discharges in hippocampal slices: an initial phase of short duration discharges followed by a phase of prolonged discharges. We assessed the involvement of transient rec...
journal_title:Journal of neurochemistry
pub_type: 杂志文章
doi:10.1111/j.1471-4159.2006.04377.x
更新日期:2007-04-01 00:00:00