The role of poly(ADP-ribose) polymerase (PARP) in oxidative cell death - Several neurodegenerative disorders, including stroke, Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Parkinson's Disease are associated with elevated oxidative stress in brain tissues. PARP is an abundant nuclear enzyme normally involved in DNA stability and repair and integrity. However, oxidative DNA damage leads to excessive PARP activation, massive depletion of cellular energy currencies, and eventual cell death. Amazingly, genetic deletion of PARP expression prevents neuron death in rodent stroke models, indicating an important role for PARP in ischemic cell death and suggesting that blocking PARP may be a useful therapeutic strategy in the treatment of stroke. Moreover, several studies suggest that PARP activation is likely a mechanism of cell death that is common to multiple neurodegenerative disorders. My laboratory is interested in deciphering mechanisms by which PARP contributes to the death of neurons and glial cells in conditions simulating cerebral ischemia and other neurodegenerative disorders. We are currently particularly interested in mechanisms that selectively activate astrocyte PARP and the associated effects on astrocyte bioenergetics and glutamate homeostasis.
Mechanisms of glutamate flux in brain - Glutamate is the major exictatory neurotransmitter in brain. Interstitial glutamate levels are tightly regulated by high affinity glutamate transporters expressed on astrocytes to maintain optimal synaptic function. Reduced glutamate uptake or enhanced cellular glutamate efflux results in excessive stimulation of glutamate receptors and nerve cell death. This mechanism of nerve cell death causes or is at least associated with pathologies of several neurodegenerative disorders, including stroke, brain/spinal cord trauma and Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease). My laboratory is interested in studying how expression and function of astrocyte and neuron glutamate transport is regulated, particularly in neurodegenerative disorders. We are also focused on identifying novel mechanisms of glutamate efflux in brain, and assessing their importance in glutamate homeostasis in neurodegenerative disorders.
Intercellular communication in brain - While astrocytes have been historically thought of as support cells for neurons, recent developments have proven otherwise by illustrating that astrocytes can receive pre-synaptic input, release neurotransmitters in a vesicular-like fashion, and in turn directly influence crucial parameters such as neuronal excitability, synaptic plasticity and activity-dependent cerebral blood flow. In addition, astrocytes communicate with one another by propagating waves of elevated extracellular Ca2+ from cell to cell. This process has been shown to be mediated by gap junction proteins and extracellular ATP signaling. My laboratory is interested in all aspects of cell to cell communication involving astrocytes. At this time specific focus is being placed on determining when and how ATP is released from astrocytes and the role purinergic signaling and gap junction proteins play in spreading signals throughout brain initiated by energy failure characteristic of cerebral ischemia.
1. LeMaistre, J.L. and Anderson, C.M. Custom astrocyte-mediated vasomotor responses to neuronal energy demand. Genome Biol. 10 (2009) 209-209.5.
2. Gliddon, C.M., Shao, Z., LeMaistre, J.L. and Anderson, C.M. Cellular distribution of the neutral amino acid transporter ASCT2 in mouse brain. J. Neurochem. 108 (2009) 372- 83.
3. Suh, S.W., Aoyama, K., Alano, C., Anderson, C.M., Hamby, A. and Swanson, R.A. Zinc inhibits astrocyte glutamate uptake by activation of poly(ADP-ribose) polymerase-1. ol Med. 13 (2007) 344-349. Impact factor 2.71
4. Suh, S.W., Bergher, J., Anderson, C.M., Treadway, J.L., Fosgerau, K. and Swanson, R.A. Astrocyte glycogen maintains neuronal activity during hypoglycaemia: studies with the glycogen phosphorylase inhibitor CP-316,819. J. Pharmacol. Exp. Ther. 321 (2007) 40-50.
5. Anderson, C.M. and Nedergaard, M. Emerging challenges of assigning P2X7 receptor function and immunoreactivity in neurons. Trends Neurosci. 29 (2006) 257-262. [6. Anderson, C.M., Bergher, J. and Swanson R.A. ATP-induced ATP release from astrocytes. J. Neurochem. 88 (2004) 246-256.
Accepted or in press refereed papers:
1. Shao, Z., Kamboj, A. and Anderson, C.M. Functional and immunocytochemical characterization of D-serine transporters in cortical neuron and astrocyte cultures. J. Neurosci. Res. In Press.
Submitted refereed papers:
1. Tang, K.S., Suh, S.W., Alano, C.C., Hunt, W.T., Swanson, R.A. and Anderson, C.M. Astrocyte poly(ADP-ribose) polymerase-1 (PARP-1) activation leads to bioenergetic depletion and inhibition of glutamate uptake capacity. Submitted to Glia
Published contributions to a collective work and book chapters:
1. Tang, K.S., Suh, S.W., Swanson, R.A. and Anderson, C.M. Bioenergetic consequences of poly(ADP-ribose) polymerase-1 activation. The VIII European Meeting – Glial Cells in Health and Disease. London, United Kingdom, September 4-8, 2007; 113-116 16 March 2, 2009
Presentations as guest speaker:
1. Anderson, C.M., LeMaistre, J.L., Gliddon, C.M. and Shao, Z. Evidence for vasoactive endothelial NMDA receptors in cerebral vasculature. Canadian Institute of Neuroscience, Mental Health and Addiction advisory board meeting. Winnipeg, MB (2007).
2. Anderson, C.M., LeMaistre, J.L., Gliddon, C.M. and Shao, Z. Vasoactive endothelial NMDA receptors in mouse brain. University of Western Ontario, Department of Physiology, Pharmacology and Toxicology. London, ON (2007).
3. Anderson, C.M., LeMaistre, J.L., Gliddon, C.M. and Shao, Z. Regulation of gliotransmitter release. Canadian Association of Neuroscience Annual Meeting. Toronto, ON (2007). delivered by Richard Robitaille due to birth of child.
4. Anderson, C.M., Duan, S. and Swanson, R.A. P2X7-mediated gliotransmitter release.Gliotransmitters minisymposium at Society for Neuroscience annual meeting, San Diego, CA (2004).
1. Hunt, W.T., Anderson, H.D. and Anderson, C.M. Post-treatment protection by Conjugated Linoleic Acid against glutamate induced excitotoxicity. Canadian Association for Neuroscience Annual Meeting, Montréal, Canada (2008).
2. LeMaistre, J.L, Anderson, H.D. and Anderson, C.M. NMDA receptor agonists dilate isolated mouse cerebral arteries by an eNOS mediated mechanism. Canadian Association for Neuroscience Annual Meeting, Montréal, Canada (2008).
3. Tang, K.S., Suh, S.W., Alano, C.C., Swanson, R.A. and Anderson, C.M.. Astrocyte poly(ADPribose) polymerase-1 activation causes glutamate excitotoxicity in neurons. The Third ISN Special Neurochemistry Conference - 8th International Meeting for Brain Energy Metabolism – "Neurodegeneration and Regeneration" (2008) P1-02-16: 60; Beijing, China.
4. Tang, K.S., Suh, S.W., Swanson, R.A. and Anderson, C.M. Severe inhibition of glutamate uptake by PARP-1-induced ATP depletion in astrocytes. Soc Neurosci. Abs. (2007) 33:579.8. Society for Neuroscience Annual Meeting, San Diego, CA.
5. Shao, Z., Gliddon, C.M. and Anderson, C.M. Expression of D-serine transporters in mouse brain cultures and slices. Soc. Neurosci. Abs. (2007) 33:579.21. Society for Neuroscience Annual Meeting, San Diego, CA.
6. LeMaistre, J.L., Anderson, H.D. and Anderson, C.M. NMDA receptor-mediated dilation of isolated mouse middle cerebral arteries by glutamate and D-serine. Soc. Neurosci. Abs. (2007) 33:875.24. Society for Neuroscience Annual Meeting, San Diego, CA.
7. Hunt, W.T. and Anderson, C.M. Conjugated Linoleic Acid (CLA) protects cultured embryonic cortical neurons from glutamate toxicity. Soc. Neurosci. Abs. (2007) 33:380.23. Society for Neuroscience Annual Meeting, San Diego, CA. 17 March 2, 2009
8. Tang, K.S., Suh, S.W., Swanson, R.A. and Anderson, C.M. PARP-1 activation causes bioenergetic depletion and impaired glutamate uptake capacity in cultured mouse astrocytes. Neuron Glia Biology (2007) 3 (Suppl. 1): S66. European Glial Cell Meeting, London, UK.
9. Shao, Z. and Anderson, C.M. D-Serine transport in neurons and astrocytes. Acta Pharmacologica Sinica (2006) Supp. 1:103. 16th International Union of Pharmacology 2006 Meeting, Beijing, China.
10. Swanson, R.A., Berger, J.P., Suh, S.W. and Anderson, C.M. Manipulation of brain glycogen levels in vivo: effects on neuron function and survival during severe hypoglycaemia. J. Neurochem. (2005) 94, Supp. 1:W04-02. 36th Annual Meeting of the American Society for
Neurochemistry, Madison, WI. 11. Scemes, E., Rouach, N., Newman, E.A., Contreras, J., Ye, Z., Anderson, C.M. and Parpura, V. Neuroglia interactions: mechanisms involved in glial release of transmitters. Soc. Neurosci. Abstr. (2004) 30:7. Society for Neuroscience Annual Meeting, San Diego, CA.