A5041209867- Neuroscience and Neuropharmacology Research
- Cellular transport and secretion
- Axon Guidance and Neuronal Signaling
- Receptor Mechanisms and Signaling
- Nerve injury and regeneration
- Neuroinflammation and Neurodegeneration Mechanisms
- Neurogenesis and neuroplasticity mechanisms
- Wnt/β-catenin signaling in development and cancer
- Genetics and Neurodevelopmental Disorders
- Lipid Membrane Structure and Behavior
- Adipose Tissue and Metabolism
- Ubiquitin and proteasome pathways
- Regulation of Appetite and Obesity
- RNA and protein synthesis mechanisms
- Pancreatic function and diabetes
- Amyotrophic Lateral Sclerosis Research
- Ion channel regulation and function
- Biotin and Related Studies
- Cardiac electrophysiology and arrhythmias
- Glycosylation and Glycoproteins Research
- RNA Interference and Gene Delivery
- PI3K/AKT/mTOR signaling in cancer
- Mitochondrial Function and Pathology
- Epigenetics and DNA Methylation
- Hippo pathway signaling and YAP/TAZ
University of British Columbia
2015-2025
Vancouver Coastal Health
2019-2020
Czech Academy of Sciences, Institute of Physiology
2008
Howard Hughes Medical Institute
2003-2006
University of California, San Francisco
2003-2006
Montreal Neurological Institute and Hospital
1996-1999
McGill University
1996-1999
Différenciation et Communication Neuronale et Neuroendocrine
1997
University of Toronto
1995
Abstract. To determine whether the p75 neurotrophin receptor (p75NTR) plays a role in naturally occurring neuronal death, we examined neonatal sympathetic neurons that express both TrkA tyrosine kinase and p75NTR. When neuron survival is maintained with low quantities of NGF or KCl, brain-derived neurotrophic factor (BDNF), which does not activate Trk receptors on neurons, causes apoptosis increased phosphorylation c-jun. Function-blocking antibody studies indicate this due to BDNF-mediated...
Naturally occurring sympathetic neuron death is the result of two apoptotic signaling events: one normally suppressed by NGF/TrkA survival signals, and a second activated p75 neurotrophin receptor. Here we demonstrate that p53 tumor suppressor protein, likely as induced MEKK-JNK pathway, an essential component both these cascades. In cultured neonatal neurons, protein levels are elevated in response to NGF withdrawal p75NTR activation. also results elevation known target, Bax. Functional...
We have asked whether p75(NTR) may play a role in neuronal apoptosis by producing transgenic mice that express the intracellular domain within peripheral and central neurons. These animals showed profound reductions numbers of sympathetic sensory neurons as well cell loss neocortex, where there is normally little or no expression. Developmental facial motor was not observed, but induced expression adult led to increased neuron death after axotomy. Biochemical analyses suggest these effects...
Neurons of the vertebrate central nervous system have capacity to modify synapse number, morphology, and efficacy in response activity. Some these functions can be attributed activity-induced synthesis secretion neurotrophin brain-derived neurotrophic factor (BDNF); however, molecular mechanisms by which BDNF mediates events are still not well understood. Using time-lapse confocal analysis, we show that mobilizes synaptic vesicles at existing synapses, resulting small clusters “splitting”...
Abstract Synaptic plasticity is mediated by the dynamic localization of proteins to and from synapses. This controlled, in part, through activity-induced palmitoylation synaptic proteins. Here we report that ability palmitoyl-acyl transferase, DHHC5, palmitoylate substrates an activity-dependent manner dependent on changes its subcellular localization. Under basal conditions, DHHC5 bound PSD-95 Fyn kinase, stabilized at membrane Fyn-mediated phosphorylation a tyrosine residue within...
In this report, we have tested the hypothesis that brain-derived neurotrophic factor (BDNF) is an anterograde in CNS and focused on central noradrenergic neurons synthesize BDNF. Double-label immunocytochemistry for BDNF dopamine-β-hydroxylase (DBH), a marker neurons, demonstrated partially localized to nerve fibers terminals adult rat brain. To test functional importance of BDNF, analyzed transgenic mice carrying DBH–BDNF minigene. Increased synthesis caused elevated TrkB tyrosine kinase...
Perturbations in neuregulin-1 (NRG1)/ErbB4 function have been associated with schizophrenia. Affected patients exhibit altered levels of these proteins and display hypofunction glutamatergic synapses as well neuronal circuitry. However, the role NRG1/ErbB4 regulating synapse maturation process formation has not extensively examined. Here we demonstrate that ErbB4 is expressed inhibitory interneurons at both excitatory postsynaptic sites. Overexpression postsynaptically enhances size but...
Palmitoylation is a post-translational lipid modification involving the attachment of 16-carbon saturated fatty acid, palmitate, to cysteine residues substrate proteins through labile thioester bond [reviewed in1]. protein increases its hydrophobicity, and typically facilitates trafficking toward cellular membranes. Recent studies have shown palmitoylation be one most common modifications in neurons1, 2, suggesting that palmitate turnover an important mechanism by which these cells regulate...
Frontotemporal dementia (FTD) has been linked to mutations in the progranulin gene ( GRN ) that lead (PGRN) haploinsufficiency. Thus far, our understanding of effects PGRN depletion brain derived from investigation gross pathology, and more detailed analyses cellular function have lacking. We report knocking down levels rat primary hippocampal cultures reduces neural connectivity by decreasing neuronal arborization length as well synapse density. Despite this, number synaptic vesicles per...
The cadherin/β-catenin adhesion complex is a key mediator of the bidirectional changes in synapse strength which are believed to underlie learning and memory. In present study, we demonstrate that stabilization β-catenin hippocampus adult mice results significant impairments cognitive flexibility spatial reversal learning, including impaired extinction during phase Morris water maze deficits delayed nonmatch place T-maze task. accordance with these deficits, was found abolish long-term...
Significance Consumption of palatable food or food-related advertising can prime increased intake, potentially leading to overeating. We show that short-term exposure foods induces long-lasting synaptic plasticity in mesolimbic dopamine neurons. Furthermore, sweetened high-fat drive approach behaviors and consumption days after the initial exposure. Suppressing excitatory transmission ventral tegmental area reverse consumption. Targeting this circuit with brain-delivered insulin may provide...
Astrocytes express neurotransmitter receptors that serve as sensors of synaptic activity and initiate signals leading to activity-dependent local vasodilation increases in blood flow. We previously showed arteriolar produced by activation cortical astrocytes is dependent on endothelial nitric oxide synthase (eNOS) endogenous agonists N-methyl-D-aspartate (NMDA) receptors. Here, we tested the hypothesis these effects are mediated NMDA expressed brain cells. Primary cultures receptor subunits...
Abstract Functional variomics provides the foundation for personalized medicine by linking genetic variation to disease expression, outcome and treatment, yet its utility is dependent on appropriate assays evaluate mutation impact protein function. To fully assess effects of 106 missense nonsense variants PTEN associated with autism spectrum disorder, somatic cancer hamartoma syndrome (PHTS), we take a deep phenotypic profiling approach using 18 in 5 model systems spanning diverse cellular...
An understanding of how synaptic vesicles are recruited to and maintained at presynaptic compartments is required discern the molecular mechanisms underlying assembly plasticity. We have previously demonstrated that cadherin–β-catenin complexes cluster sites. Here we show scribble interacts with complex coordinate vesicle localization. Scribble β-catenin colocalized synapses can be coimmunoprecipitated from neuronal lysates, indicating an interaction between synapse. Using RNA interference...
Semaphorins are known to play an important role in axon guidance and growth by triggering dynamic rearrangements of the actin cytoskeleton neuronal cone. Intriguingly, some these molecules persistently expressed after axonal pathfinding target recognition completed. Although their function at later stages is poorly understood, recent findings suggest a for proteins regulating synaptic connections. Here we demonstrate that semaphorin 5B (Sema5B) regulates elimination connections cultured...
Presynaptic compartments are formed through the recruitment of preassembled clusters proteins to points cell—cell contact, however, molecular mechanism(s) underlying this process remains unclear. We demonstrate that polymerized actin can recruit and maintain synaptic vesicles discrete sites along axon, cadherin/β-catenin/scribble/β-pix complexes play an important role in event. Previous work has demonstrated β-catenin scribble for clustering at synapses. β-pix, a Rac/Cdc42 guanine nucleotide...
Palmitoylation is a reversible post-translational lipid modification that facilitates vesicular transport and subcellular localization of modified proteins. This process catalyzed by ZDHHC enzymes are implicated in several neurological neurodevelopmental disorders. Loss-of-function mutations ZDHHC9 have been identified patients with X-linked intellectual disability (XLID) associated increased epilepsy risk. Loss Zdhhc9 function hippocampal cultures leads to shorter dendritic arbors fewer...