Abstract:
:In Alzheimer's disease (AD), excessive amounts of quinolinic acid (QUIN) accumulate within the brain parenchyma and dystrophic neurons. QUIN also regulates glutamate uptake into neurons, which may be due to modulation of Na+-dependent excitatory amino acid transporters (EAATs). To determine the biological relationships between QUIN and glutamate dysfunction, we first quantified the functionality and kinetics of [3H]QUIN uptake in primary human neurons using liquid scintillation. We then measured changes in the protein expression of the glutamate transporter EAAT3 and EAAT1b in primary neurons treated with QUIN and the EAAT inhibitor L-trans-pyrrolidine-2,4-dicarboxylic acid (2,4-PDC) using western blotting and immunohistochemistry. Immunohistochemistry was further used to elucidate intracellular transport of exogenous QUIN and the lysosomal-associated membrane protein 2 (LAMP2). Structural insights into the binding between QUIN and EAAT3 were further investigated using molecular docking techniques. We report significant temperature-dependent high-affinity transport leading to neuronal uptake of [3H]QUIN with a Km of 42.2 μM, and a Vmax of 9.492 pmol/2 min/mg protein, comparable with the uptake of glutamate. We also found that QUIN increases expression of the EAAT3 monomer while decreasing the functional trimer. QUIN uptake into primary neurons was shown to involve EAAT3 as uptake was significantly attenuated following EAAT inhibition. We also demonstrated that QUIN increases the expression of aberrant EAAT1b protein in neurons further implicating QUIN-induced glutamate dysfunction. Furthermore, we demonstrated that QUIN is metabolised exclusively in lysosomes. The involvement of EAAT3 as a modulator for QUIN uptake was further confirmed using molecular docking. This study is the first to characterise a mechanism for QUIN uptake into primary human neurons involving EAAT3, opening potential targets to attenuate QUIN-induced excitotoxicity in neuroinflammatory diseases.
journal_name
Mol Neurobioljournal_title
Molecular neurobiologyauthors
Braidy N,Alicajic H,Pow D,Smith J,Jugder BE,Brew BJ,Nicolazzo JA,Guillemin GJdoi
10.1007/s12035-020-02046-6subject
Has Abstractpub_date
2021-01-01 00:00:00pages
34-54issue
1eissn
0893-7648issn
1559-1182pii
10.1007/s12035-020-02046-6journal_volume
58pub_type
杂志文章abstract::The epidermal growth factor (EGF) family of polypeptides is regulators for tissue development and repair, and is characterized by the fact that their mature forms are proteolytically derived from their integral membrane precursors. This article reviews roles of the prominent members of the EGF family (EGF, transformin...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1007/BF02742440
更新日期:1999-10-01 00:00:00
abstract::Atonal genes are basic helix-loop-helix transcription factors that were first identified as regulating the formation of mechanoreceptors and photoreceptors in Drosophila. Isolation of vertebrate homologs of atonal genes has shown these transcription factors to play diverse roles in the development of neurons and their...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-014-8925-0
更新日期:2015-12-01 00:00:00
abstract::The transition from occasional to escalated psychostimulant use is accelerated by prior drug exposure. These behavioral observations may be related to long-lasting transcriptional and/or epigenetic changes induced by the drug pre-exposure. Herein, we investigated if a single methamphetamine (METH) injection would enha...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-019-01830-3
更新日期:2020-03-01 00:00:00
abstract::Neural stem cells (NSCs) are hitherto regarded as perspective candidates for cell transplantation in clinical therapies for multilevel spinal cord injury and function restoration. However, the extreme drawbacks of NSCs available for injury transplantation still represent a significant bottleneck in neural regeneration...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-016-0057-2
更新日期:2017-01-01 00:00:00
abstract::OMI/HTRA2 (high-temperature requirement serine protease A2) is a mitochondrial serine protease involved in several cellular processes, including autophagy, chaperone activity, and apoptosis. Few studies on the role of OMI/HTRA2 in Alzheimer's disease (AD) are available, but none on its relationship with the cholinergi...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-018-1383-3
更新日期:2019-07-01 00:00:00
abstract::Fenpropathrin is one of the widely used pyrethroids in agriculture and household and also reported to have neurotoxic effects in rodent models. In our Parkinson's disease (PD) clinic, there was a unique patient with a history of daily exposure to fenpropathrin for 6 months prior to developing Parkinsonian symptoms pro...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-014-9057-2
更新日期:2016-03-01 00:00:00
abstract::Tissue acidosis is a common feature in many pathological conditions. Activation of acid-sensing ion channel 1a (ASIC1a) plays a key role in acidosis-mediated neurotoxicity. Protein kinase C (PKC) activity has been proved to be associated with many physiological processes and pathological conditions; however, whether P...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-020-02056-4
更新日期:2020-11-01 00:00:00
abstract::Major depression is a serious side effect of interferon-α (IFN-α), which is used in the therapy of hepatitis C virus (HCV) infection. Due to the lack of reproducible animal models, the mechanisms underlying IFN-α-related depression are largely unknown. We herein established a mouse model, in which murine IFN-α (250 IU...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-014-8861-z
更新日期:2015-08-01 00:00:00
abstract::Light triggers a sequence of events that damage photoreceptor cells within the superior central portion of the retina, resulting in apoptotic cell death. This damage is mediated by energy absorbed by rhodopsin and the intermediates of the rhodopsin-bleaching process. Furthermore, inhibition of the visual cycle and the...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1385/MN:28:2:111
更新日期:2003-10-01 00:00:00
abstract::The development of in vitro amplification systems allows detecting femtomolar amounts of prion protein scrapie (PrP(Sc)) in human cerebrospinal fluid (CSF). We performed a CSF study to determine the effects of prion disease type, codon 129 genotype, PrP(Sc) type, and other disease-related factors on the real-time quak...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-014-8709-6
更新日期:2015-02-01 00:00:00
abstract::There is accumulating evidence on the use of N-acetylcysteine (NAC) in the treatment of patients with neuropsychiatric disorders. As a multi-target drug and a glutathione precursor, NAC is a promising molecule in the management of stress-related disorders, for which there is an expanding field of research investigatin...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-018-1165-y
更新日期:2019-02-01 00:00:00
abstract::The drastic increase in the consumption of fructose encouraged the research to focus on its effects on brain physio-pathology. Although young and adults differ largely by their metabolic and physiological profiles, most of the previous studies investigated brain disturbances induced by long-term fructose feeding in ad...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-017-0518-2
更新日期:2018-04-01 00:00:00
abstract::Neuropsin (NP) is a serine protease, implicated in synaptic plasticity and memory acquisition through cleavage of synaptic adhesion molecule, L1CAM. However, NP has not been explored during brain aging that entails drastic deterioration of plasticity and memory with selective regional vulnerability. Therefore, we have...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-014-8780-z
更新日期:2015-01-01 00:00:00
abstract::Statins have proven their effectiveness in the treatment of cardiovascular disease. This class of drugs has also attracted attention as a potential treatment for dissimilar diseases such as certain types of cancers and neurodegenerative diseases. What appears to be a contradiction is that, in the case of cancer, it ha...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1007/s12035-013-8496-5
更新日期:2013-10-01 00:00:00
abstract::Cerebral ischemia is a cerebrovascular episode that generates a high incidence of death and physical and mental disabilities worldwide. Excitotoxicity, release of free radicals, and exacerbated immune response cause serious complications in motor and cognitive areas during both short and long time frames post-ischemia...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-016-0162-2
更新日期:2017-11-01 00:00:00
abstract::Despite the increasing evidence of eye abnormalities, the effects of prenatal exposure to cocaine on the visual system are still poorly understood. This study was aimed at analyzing the qualitative and quantitative organization of the retinal photoreceptor cells (PR) and outer nuclear layer (ONL) after prenatal exposu...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/BF02740686
更新日期:1995-08-01 00:00:00
abstract::Myeloperoxidase (MPO) has paradoxically been found to be able to both activate matrix metalloproteinases (MMPs) as well as inhibit MMPs. However, these regulatory effects have not yet been observed in vivo, and it is unclear which pathway is relevant in vivo. We aim to track MPO regulation of MMP activity in living an...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-018-1137-2
更新日期:2019-02-01 00:00:00
abstract::Alzheimer's disease is a chronic neurodegenerative disorder characterized by neuronal loss, cerebrovascular inflammation, and accumulation of senile plaques in the brain parenchyma and cerebral blood vessels. Amyloid-beta peptide (Abeta), a major component of senile plaques, has been shown to exert multiple toxic effe...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1007/s12035-010-8121-9
更新日期:2010-06-01 00:00:00
abstract::Intracerebroventricular (icv) amyloid-beta (Aβ)1-40 infusion to mice has been demonstrated to cause neurotoxicty and depressive-like behavior and it can be used to evaluate antidepressant and neuroprotective effect of drugs. Atorvastatin is a widely used statin that has demonstrated antidepressant-like effect in predi...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-016-0134-6
更新日期:2017-10-01 00:00:00
abstract::Paclitaxel is a chemotherapeutic agent used to treat solid tumours. However, it causes an acute and neuropathic pain syndrome that limits its use. Among the mechanisms involved in neuropathic pain caused by paclitaxel is activation of kinin receptors. Angiotensin converting enzyme (ACE) inhibitors can enhance kinin re...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-016-0275-7
更新日期:2017-12-01 00:00:00
abstract::Extracellular nucleotides, particularly adenosine 5'-triphosphate (ATP), act as signaling molecules in the inner ear. Roles as neurotransmitters, neuromodulators, and as autocrine or paracrine humoral factors are evident. The diversity of the signaling pathways for nucleotides, which include a variety of ATP-gated ion...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1007/BF02740601
更新日期:1998-02-01 00:00:00
abstract::Although photobiomodulation therapy (PBM) has been applied clinically for the treatment of pain and inflammation, wound healing, sports and soft tissue injuries, as well as to repair injured spinal cords and peripheral nerves, it remains unclear which molecular substrates (receptor) are implicated in the cellular mech...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-017-0792-z
更新日期:2018-07-01 00:00:00
abstract::Conventional antidepressant drugs elevate the availability of monoamine neurotransmitters. However, these pharmacological therapies have limited efficacy and a slow onset of action as main limitations. New glutamatergic drugs such as ketamine have shown promise as a rapid-acting antidepressant drugs although with adve...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-020-01954-x
更新日期:2020-08-01 00:00:00
abstract::The gammaretroviral human endogenous retrovirus (HERV) families MRSV/HERV-W and HERV-H (including the closely related HERV-Fc1) are associated with an increased risk of multiple sclerosis (MS). Complete HERV sequences betray their endogenous retroviral origin, with open reading frames in gag, pro, pol and env being fl...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1007/s12035-018-1255-x
更新日期:2019-04-01 00:00:00
abstract::The identification of causative mutations in the (pro)granulin gene (GRN) has been a major breakthrough in the research on frontotemporal dementia (FTD). So far, all FTD-associated GRN mutations are leading to neurodegeneration through a "loss-of-function" mechanism, encouraging researchers to develop a growing number...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1007/s12035-012-8380-8
更新日期:2013-02-01 00:00:00
abstract::Hypertension is one of the co-morbid conditions for stroke and profoundly increases its incidence. Angiotensin II (AngII) is shown to be at the center stage in driving the renin angiotensin system via activation of angiotensin 1 receptor (AT1R). This makes the AT1R gene one of the candidates whose differential regulat...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-015-9109-2
更新日期:2016-04-01 00:00:00
abstract::In this study, we investigated the influence of elevated RAS expression on the growth of meningioma in vivo and in vitro. The IOMM-LEE cells, representing a cell line derived from malignant meningioma, were divided into blank control group (cells without any drug treatment), negative control group (cells treated with ...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-016-9763-z
更新日期:2017-01-01 00:00:00
abstract::Peripheral nerve injury requires optimal conditions in both macro-environment and microenvironment for promotion of axonal regeneration. However, most repair strategies of traumatic peripheral nerve injury often lead to dissatisfying results in clinical outcome. Though various strategies have been carried out to impro...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-018-1172-z
更新日期:2019-03-01 00:00:00
abstract::Neuroinflammation is the primary response by immune cells in the nervous system to protect against infection. Chronic and uncontrolled neuroinflammation triggers neuronal injury and neuronal death resulting in a variety of neurodegenerative disorders. Therefore, fine tuning of the immune response in the nervous system...
journal_title:Molecular neurobiology
pub_type: 杂志文章,评审
doi:10.1007/s12035-020-02066-2
更新日期:2020-11-01 00:00:00
abstract::Based on a multimodal drug design strategy for age-related neurodegenerative diseases, we have synthesized a multifunctional nontoxic, brain-permeable iron-chelating compound, M30, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase-B inhibitor, rasagiline and the antioxi...
journal_title:Molecular neurobiology
pub_type: 杂志文章
doi:10.1007/s12035-012-8304-7
更新日期:2012-08-01 00:00:00