Mechanisms of aquaporin-4 vesicular trafficking in mammalian cells.

The aquaporin-4 (AQP4) water channel is abundantly expressed in the glial cells of the central nervous system and facilitates brain swelling following diverse insults, such as traumatic injury or stroke. Lack of specific and therapeutic AQP4 inhibitors highlights the need to explore alternative routes to control the water permeability of glial cell membranes. The cell surface abundance of AQP4 in mammalian cells fluctuates rapidly in response to changes in oxygen levels and tonicity, suggesting a role for vesicular trafficking in its translocation to and from the cell surface.

An Extracellular/Membrane-Bound S100P Pool Regulates Motility and Invasion of Human Extravillous Trophoblast Lines and Primary Cells.

Whilst S100P has been shown to be a marker for carcinogenesis, we have shown, in non-physio-pathological states, that its expression promotes trophoblast motility and invasion but the mechanisms explaining these cellular processes are unknown. Here we identify the presence of S100P in the plasma membrane/cell surface of all trophoblast cells tested, whether lines, primary extravillous (EVT) cells, or section tissue samples using either biochemical purification of plasma membrane material, cell surface protein isolation through biotinylation, or microscopy analysis. Using extracellular loss of function studies, through addition of a specific S100P antibody, our work shows that inhibiting the cell surface/membrane-bound or extracellular S100P pools significantly reduces, but importantly only in part, both cell motility and cellular invasion in different trophoblastic cell lines, as well as primary EVTs.

Bypassing mitochondrial defects rescues Huntington's phenotypes in Drosophila.

Huntington's disease (HD) is a fatal neurodegenerative disease with limited treatment options. Human and animal studies have suggested that metabolic and mitochondrial dysfunctions contribute to HD pathogenesis. Here, we use high-resolution respirometry to uncover defective mitochondrial oxidative phosphorylation and electron transfer capacity when a mutant huntingtin fragment is targeted to neurons or muscles in Drosophila and find that enhancing mitochondrial function can ameliorate these defects.

Kynurenine 3-Monooxygenase Interacts with Huntingtin at the Outer Mitochondrial Membrane.

The flavoprotein kynurenine 3-monooxygenase (KMO) is localised to the outer mitochondrial membrane and catalyses the synthesis of 3-hydroxykynurenine from L-kynurenine, a key step in the kynurenine pathway (KP) of tryptophan degradation. Perturbation of KP metabolism due to inflammation has long been associated with the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD)-which is caused by the expansion of a polyglutamine stretch in the huntingtin (HTT) protein. While HTT is primarily localised to the cytoplasm, it also associates with mitochondria, where it may physically interact with KMO.

Chemokine CXCL12 drives pericyte accumulation and airway remodeling in allergic airway disease.

Background: Airway remodeling is a significant contributor to impaired lung function in chronic allergic airway disease. Currently, no therapy exists that is capable of targeting these structural changes and the consequent loss of function. In the context of chronic allergic inflammation, pericytes have been shown to uncouple from the pulmonary microvasculature, migrate to areas of inflammation, and significantly contribute to airway wall remodeling and lung dysfunction.

DJ-1 in Parkinson's Disease: Clinical Insights and Therapeutic Perspectives.

Mutations in the protein DJ-1 cause autosomal recessive forms of Parkinson's disease (PD) and oxidized DJ-1 is found in the brains of idiopathic PD individuals. While several functions have been ascribed to DJ-1 (most notably protection from oxidative stress), its contribution to PD pathogenesis is not yet clear. Here we provide an overview of the clinical research to date on DJ-1 and the current state of knowledge regarding DJ-1 characterization in the human brain.

Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice: Relevance to Psychotic Disorders.

Background: Kynurenine 3-monooxygenase converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway-which is implicated as dysfunctional in various psychiatric disorders-toward enhanced synthesis of kynurenic acid, an antagonist of both α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors. Possibly as a result of reduced kynurenine 3-monooxygenase activity, elevated central nervous system levels of kynurenic acid have been found in patients with psychotic disorders, including schizophrenia.

Methods: In the present study, we investigated adaptive-and possibly regulatory-changes in mice with a targeted deletion of Kmo (Kmo) and characterized the kynurenine 3-monooxygenase-deficient mice using six behavioral assays relevant for the study of schizophrenia.

Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in Huntington's disease.

Huntington's disease (HD) is a devastating neurodegenerative disorder which is inherited in an autosomal dominant manner. HD is caused by a trinucleotide CAG repeat expansion that encodes a polyglutamine stretch in the huntingtin (HTT) protein. Mutant HTT expression leads to a myriad of cellular dysfunctions culminating in neuronal loss and consequent motor, cognitive and psychiatric disturbances in HD patients.

Parkinson's disease-associated mutations in DJ-1 modulate its dimerization in living cells.

Mutations in the protein DJ-1 cause recessive forms of early onset familial Parkinson's disease (PD). To date, most of the causative mutations studied destabilize formation of DJ-1 homodimers, which appears to be closely linked to its normal function in oxidative stress and other cellular processes. Despite the importance of understanding the dimerization dynamics of this protein, this aspect of DJ-1 biology has not previously been directly studied in living cells.

Specific inhibition of the JNK pathway promotes locomotor recovery and neuroprotection after mouse spinal cord injury.

Limiting the development of secondary damage represents one of the major goals of neuroprotective therapies after spinal cord injury. Here, we demonstrate that specific JNK inhibition via a single intraperitoneal injection of the cell permeable peptide D-JNKI1 6h after lesion improves locomotor recovery assessed by both the footprint and the BMS tests up to 4 months post-injury in mice. JNK inhibition prevents c-jun phosphorylation and caspase-3 cleavage, has neuroprotective effects and results in an increased sparing of white matter at the lesion site.

c-Jun N-terminal kinase (JNK) and p38 play different roles in age-related Purkinje cell death in murine organotypic culture.

Several studies have shown that Purkinje cells die by apoptosis in organotypic slice cultures from postnatal 3-day-old (P3) mice. This cell death is age-dependent and has been proposed as indirect evidence for the programmed Purkinje cell death occurring in in vivo cerebellum. Here, we studied whether c-jun N-terminal kinase (JNK) and p38 kinase pathways contribute to the Purkinje cell death observed in cerebellar slice cultures obtained from P3 mice.

Role of Glycogen Synthase Kinase-3β in APP Hyperphosphorylation Induced by NMDA Stimulation in Cortical Neurons.

The phosphorylation of Amyloid Precursor Protein (APP) at Thr plays a key role in APP metabolism that is highly relevant to AD. The c-Jun-N-terminal kinase (JNK), glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (Cdk5) can all be responsible for this phosphorylation. These kinases are activated by excitotoxic stimuli fundamental hallmarks of AD.

Age-dependent impairment of spine morphology and synaptic plasticity in hippocampal CA1 neurons of a presenilin 1 transgenic mouse model of Alzheimer's disease.

Presenilin 1 (PS1) mutations are responsible for a majority of early onset familial Alzheimer's disease (FAD) cases, in part by increasing the production of Abeta peptides. However, emerging evidence suggests other possible effects of PS1 on synaptic dysfunction where PS1 might contribute to the pathology independent of Abeta. We chose to study the L286V mutation, an aggressive FAD mutation which has never been analyzed at the electrophysiological and morphological levels.

Specific JNK inhibition by D-JNKI1 protects Purkinje cells from cell death in Lurcher mutant mouse.

In the Lurcher mutant mouse (+/Lc), Purkinje cells (PCs) selectively die due to the mutation that converts alanine to threonine in the glutamate ionotropic receptor GRID 2, thus resulting in a constitutively leaky cation channel. This intrinsic cell death determines a target-dependent cell death of granule cells and olivary neurons and cerebellum cytoarchitecture is severely disrupted in the adult Lurcher mutant. Although the +/Lc mutant has been widely characterized, less is known about the molecules involved in +/Lc PC death.

Neuronal death and neuroprotection: a review.

To achieve neuroprotection is one of the main interests for neuroscientist: understanding the control mechanisms of neuronal death allows developing new tools for preventing it. Neuronal death plays a critical role in most of the important neural pathologies, including stroke, epilepsy, Parkinson's disease and Alzheimer's disease. This review summarizes the three main different types of neuronal death: apoptosis, necrosis and autophagic cell death, although we are conscious that if cell death falls into several categories, the boundaries are not always distinct.

Recombinant human TNF-binding protein-1 (rhTBP-1) treatment delays both symptoms progression and motor neuron loss in the wobbler mouse.

TNF-alpha overexpression may contribute to motor neuron death in amyotrophic lateral sclerosis (ALS). We investigated the intracellular pathway associated with TNF-alpha in the wobbler mouse, a murine model of ALS, at the onset of symptoms. TNF-alpha and TNFR1 overexpression and JNK/p38MAPK phosphorylation occurred in neurons and microglia in early symptomatic mice, suggesting that this activation may contribute to motor neuron damage.

JNK pathway as therapeutic target to prevent degeneration in the central nervous system.

JNKs (c-Jun N- terminal kinases) are important transducing enzymes involved in many faces of cellular regulation such as gene expression, cell proliferation and programmed cell death. The activation of JNK pathway is critical for naturally occurring neuronal death during development as well as for pathological death of adult brain following different insults. In particular, JNKs play an important role in excitotoxicity and all related phenomena.

A peptide inhibitor of c-Jun N-terminal kinase protects against excitotoxicity and cerebral ischemia.

Neuronal death in cerebral ischemia is largely due to excitotoxic mechanisms, which are known to activate the c-Jun N-terminal kinase (JNK) pathway. We have evaluated the neuroprotective power of a cell-penetrating, protease-resistant peptide that blocks the access of JNK to many of its targets. We obtained strong protection in two models of middle cerebral artery occlusion (MCAO): transient occlusion in adult mice and permanent occlusion in 14-d-old rat pups.

Cyclooxygenase-2 and caspase 3 expression in trimethyltin-induced apoptosis in the mouse hippocampus.

The neurotoxicant trimethyltin (TMT) induces massive neuronal loss in vivo in the hippocampus of rodents, accompanied by behavioral alterations. The present study investigates the pattern of cell death after in vivo administration of TMT to adult mice. In the granular cell layer of the Dentate Gyrus, TUNEL staining detected DNA fragmentation, and apoptotic bodies were also evident.