Paul Albert

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Paul Albert
Full Professor

Room: Rm. 2462 RGN
Office: 613-562-5800 ext. 8307
Work E-mail: palbert@uottawa.ca

Paul Albert

Biography

Senior Scientist, Ottawa Hospital Research Institute

Associate Director Neuroscience Program
CIHR/Novartis Michael Smith Chair in Neurosciences
Professor, Department of Medicine, Faculty of Medicine, University of Ottawa
Director, Neuroscience Graduate Program, University of Ottawa

Biographical Sketch

EDUCATION:

  • 1975-77 D.E.C., Biology, Marianopolis College, Montreal, Quebec
  • 1977-80 B.Sc., Honours, Physiology, major; Biochemistry, minor; McGill Univ., Montreal, Quebec
  • 1980-85 Ph.D., Pharmacology, Harvard University, Boston, MA

Research

Professor Albert is working in the area of molecular mechanisms of autoreceptor desensitization. Successful therapy of major depression (as well as generalized anxiety, obsessive-compulsive, and other mental disorders) using a variety of antidepressant compounds (e.g., serotonin-specific reuptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, and 5-HT1A receptor agonists) is associated with a three-week time course before clinical improvement may be observed. Antidepressants appear to act by directly modifying the serotonergic system which originates in the raphe nuclei of the brain. Desensitization of inhibitory 5-HT1A autoreceptors occurs following chronic (but not acute) antidepressant treatment, and allows for enhanced firing of serotonergic raphe neurons in the presence of antidepressant. The enhanced firing results in increased serotonergic neurotransmission as the post-synaptic 5-HT receptors do not desensitize to the same extent. Receptor desensitization involves several sequential steps: uncoupling (min), mediated by phosphorylation, receptor sequestration (min-hr), and down-regulation (hr-days), involving receptor degradation and/or decreased receptor synthesis.

The importance of receptor phosphorylation, G proteins, and effectors in 5-HT1A and dopamine-D2 receptor signalling and desensitization is being probed in model cellular systems using a variety of molecular approaches, including: sense and antisense transfections, mutagenesis, cDNA cloning of novel receptors/kinases, immunoblotting/epitope tagging, and functional (cAMP, calcium, secretion) assays.

The importance of transcriptional and post-transcriptional events is being probed using 5-HT1A receptor promoter constructs, DNAase protection assays, RNAase protection assays, etc., with the ultimate aim of identifying genetic sequences that may confer susceptibility to mental disorders or responsiveness to anti-depressant treatment.

Professor Albert has established research collaborations with the Royal Ottawa Hospital (Institute for Mental Health Research) to apply this work in the areas of depression, anxiety and schizophrenia. He is also a member of the Heart and Stroke Foundation of Ontario Centre for Stroke Recovery (http://www.heartandstroke-centrestrokerecovery.ca/), a collaboration to identify genetic markers of recovery.

Research Interests

5-HT1A (Serotonin-1A) receptor gene regulation and mental illness:
Hypothesis: Down-regulation of the 5-HT1A receptor gene in serotonin neurons is required for the antidepressant actions of therapeutic compounds. Understanding the proteins that regulate the 5-HT1A promoter will lead to insights on receptor regulation and provide new therapeutic targets relevant to depression, anxiety, obsessive compulsive disorder and other mental illnesses.

  • Approaches: Knockout Models: We have cloned and characterized a number of key regulators of the rat and human 5-HT1A receptor genes using luciferase reporter fusion constructs transfected in cell lines. These include Deaf1, Hes proteins, Freud-1 (CC2D1A, a mental retardation gene), and Pet-1. We are now testing in vivo the effect of knockout of these repressors on 5-HT1A expression and 5-HT activity. Ultimately we are generating conditional knockout models that will allow us to assess the importance of these regulators in depression, anxiety, and responses to antidepressant treatment.
  • Functional Genetic Polymorphisms: In addition to alteration by transcription factors, receptor expression could be modified by genetic polymorphisms. We have associated a novel polymorphism of the 5-HT1A receptor at C(-1019)G with depression, completed suicide and resistance to antidepressant treatment, and have shown that the risk allele fails to bind to repressors Deaf1 and Hes proteins. We are continuing to evaluate the functional significance of the polymorphism in depression using knockout models, and by in vitro assessments of the role of the C(-1019)G polymorphism in 5-HT1A expression.
  • Environmental Stress Models: In addition to risk alleles that alter genetic regulation, environment appears also to alter gene regulation by inducing changes in DNA methylation at specific sites. We are examining the role of stressful environment on the developmental and epigenetic regulation of the 5-HT1A receptor and on behavioral depression in the adult.
  • Multi-target transcriptional regulators: Freud-1, a strong repressor of the 5-HT1A receptor, also represses the dopamine D2 receptor gene, and suggests that a single transcription factor may coordinately regulate several neurotransmitter systems. We are examining the spectrum of genes regulated by a given repressor using a variety of approaches including identification of DNA elements, expression analysis of knockout tissues, gene arrays, etc.
  • Multi-disease risk alleles: The likelihood of depression following stroke is about 2-fold increased, while stroke is more likely in depressed subjects. Thus, a given genetic polymorphism may influence predisposition to many illnesses. We are conducting association of the functional genetic polymorphisms implicated in depression with post-stroke depression and stroke recovery.
  • Autoregulation of 5-HT1A receptor expression: We are examining the role of specific transcription factors in the down-regulation of 5-HT1A receptors upon chronic stimulation by 5-HT. This down-regulation appears crucial to allow antidepressants to enhance 5-HT activity and improve depressed behavior.

Novel G-protein signaling pathways:
Hypothesis: Serotonin and dopamine receptors act through G proteins that couple to a diversity of intracellular signals to produce opposite (stimulatory vs. Inhibitory) responses depending on the cell type. We hypothesize that these signals are mediated by cell type-specific G-protein-effector pathways and have addressed their G-protein specificity using two complementary approaches: transfection of sense vs. antisense G proteins and a rescue approach using PTX- or RGS-insensitive G protein mutants in fibroblast vs. pituitary cells. We then used the G-proteins identified to fish out the downstream effector using a yeast two hybrid approach. This has allowed us to identify two novel Gai3-regulated pathways: coupling to TNFAIP8 (and TIPE) to stimulate cell transformation and block TNFa-induced apoptosis; and signaling to Gai3-induced RASA3 activation to inhibit activation of the Ras-Raf-MEK-ERK1/2 pathway.

Gai3-TNFAIP8: this pathway appears to be anti-apoptotic, and may play a key role in coupling of G-proteins to oncogenic transformation. We are now examining which receptors and TNF related proteins trigger this pathway. Ultimately, we will examine the roles of this pathway in vivo, in oncogenesis but also in neuronal survival.
Gai3-RASA3: This pathway is critical for dopamine D2S-induced inhibition of ERK1/2, particularly in pituitary cells. We propose that it may also mediate dopamine action to inhibit ERK1/2 and its signaling in neuronal (striatal) cultures and in vivo in negative regulation of the dopamine system.
Structure-function analysis of 5-HT1A and dopamine D2 receptor signaling:
.Hypothesis: The intracellular domains are critical for the coupling and desensitization of the receptor. We hypothesize that disruption of specific interactions of these receptor domains with Ga or Gbg will selectively block particular signaling pathways. We have identified the C-terminal portion of the i2 domain as critical for the signaling of the 5-HT1A receptor to multiple Gbg pathways, and phosphorylation of this domain desensitizes the receptor. The first steps in receptor desensitization (uncoupling) may play a key role in the longterm actions of the receptor, thus we are also examining mechanisms of acute receptor regulation by phosphorylation.

Mutation of receptor sites. We are continuing to generate new 5-HT1A mutants that target specific signaling pathways for molecular characterization of receptor-G protein-coupling and receptor desensitization by protein kinase C (PKC) or agonist. We will examine the roles of these changes in vivo with the goal of generating specific inhibitors of receptor signaling.
BRET studies. We are using the BRET approach to specifically address the role of particular receptor domains in the interaction with Ga and Gbg subunits. Our results indicate that mutations that specifically uncouple the receptor disrupt the association between the receptor and that G-protein subunit.
Signal-specific blockers: based on the specificity of mutations to Ci2, we are generating several new reagents that can specifically alter the interaction of Ci2 with specific G-protein subunits to disrupt specific signaling pathways.

AWARDS AND HONOURS

  • 1996 CIHR/Novartis Michael Smith Chair in Neuroscience
  • 1999 First Annual Mentoring Award, Faculty of Medicine, University of Ottawa.
  • 2000 John Dewan Prize, Ontario Mental Health Foundation, Ontario.
  • 2008 Vice-President, Canadian College of Psychopharmacology
  • 2010 President-Elect, Canadian College of Psychopharmacology
  • 2012 President, Canadian College of Psychopharmacology
  • 2012 Schaefer Research Scholarship, Columbia University, NY

Key Words:

serotonin, dopamine, depression, schizophrenia, anxiety, neurons, repression

Fields of Interest

  • molecular mechanisms of serotonin and dopamine receptor signaling, desensitization and regulation
  • role of transcription factors, functional polymorphisms, and epigenetic changes in mental illness and antidepressant response
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