John MacDonald, Scientist
Why I Became a Scientist
Curiosity! When I was growing up I became highly interested in psychiatry as espoused by Freud and others. Abnormal behaviour begs the question of what is the mechanism of “normal” human behaviour. Although I was fascinated by the Freudian anecdotal approaches to analyzing behaviour it made me realize that there had to be a better more scientific approach to the mind. The advent of biopsychiatry and the use of drugs to treat major mental illnesses struck me as a confirmation of the experimental scientific method as the most valid approach to understanding and treating mental illness. My curiosity for understanding actual mechanisms of brain function lead me to a career in studying neurons and synapses at the most basic level.
Providing new types of pharmacological therapy for Canadians facing Stroke and Alzheimer's disease is likely the most important concern for maintaining quality of life for an aging population. With covert strokes and in age-related degenerative diseases, brain cells are lost and the ability of these cells to communicate information is impaired. Consequentially, deficits of learning and memory and in thinking abilities in general result. Alzheimer's disease is a major example characterized by changes in excitatory communication between brain cells. The MacDonald laboratory is using molecular, electrophysiological and behavioural approaches to understand the mechanisms responsible for these problems. Several critical ion channel proteins including NMDAR, TRPM2 and TRPM7 are correlated with damage in strokes, with aging and with the degenerative mechanisms underlying Alzheimer's. They are using this basic information to design potential clinical therapies for preventing the loss of function and cells in Stroke and Alzheimer’s disease.
Research Questions and Disease Implications
It is predicted that stroke will soon become the leading cause of death worldwide (about 80% are ischemic strokes). Yet the only proven mechanism for treatment is the use of “clot busting” drugs (e.g. TPA), which must be administered within 3 hours of stroke onset. Paradoxically, the reperfusion achieved by this drug may also initiate further cell damage (reperfusion injury). Clearly there is a major need to identify alternative therapeutic mechanisms. Ischemia causes a massive release of glutamate together with an inappropriate activation of a variety of glutamate non-selective cation channels. “Delayed cell death” occurs hours or days later and it is believed to be dependent upon the activity of Ca2+ permeable NMDARs. Human trials of NMDAR antagonists have proven unsuccessful. One possible explanation is that additional types of cation channels contribute to delayed cell death. This hypothesis has been validated, at least in part, by our recent work (MacDonald, Tymianski & Mori) on TRPM7 and TRPM2 channels.
Our mutual research interactions began with the discovery that one of the two major transient receptor (TRP) channels associated with cell loss, TRPM7, is a major contributor to neuron death in ischemia and stroke. Alternatively, the other TRP channel, TRPM2, may play an additional role in “delayed cell death” caused by ischemia. The goal of our joint laboratories is to build the foundation for new types of therapy that may transform the treatment ischemic stroke in humans. TRPM2 proteins are widely expressed in the mammalian central nervous system and they are prominent in the hippocampus and cortex. The pathological roles of these channels in stroke and other degenerative diseases such as Alzheimer’s is intriguing but still largely unexplored. We have discovered large TRPM-2 like currents in cultured hippocampal and cortical neurons. In contrast to previous reports in neurons we have discovered a number of novel protocols (e.g. voltage-ramps) to enhance activation of these currents. We have also discovered that the age of the cultures determines the level of expression of these currents (aged cultures are required). This is line with the MacDonald laboratory’s extensive electrophysiological and molecular expertise. Prof. Mori’s expertise is in molecular biology (regular cDNA cloning plus 2-hybrid screening and recombinant expression) and biochemistry of ion channels, especially Ca channels, and in mouse genetics (including knock-outs and spontaneous Ca channel mutant mice). He has recently extended his expertise to chemical biology (design and synthesis of labeled compounds for receptors and channels) and to molecular imaging (probes for second messenger molecules). The Mori laboratory has already succeeded in establishing TRPM2 KO mice, which shows defects in inflammatory chemokine production and neutrophil infiltration.
Providing new types of pharmacological therapy for the elderly facing Alzheimer's and related disease is likely the most important health and social concern for Canada and the developed world. With aging, covert strokes, and in age-related degenerative diseases brain cells are lost and the ability of these cells to communicate information is impaired. This results in deficits of learning and memory, and in thinking abilities in general. Alzheimer's disease is a major example of where there are changes in excitatory communication between brain cells. Our laboratory examines how a unique ion channel, TRPM2, is correlated with aging and with the degenerative mechanisms underlying Alzheimer's like conditions. It examines how TRPM2 channels interact with one of the excitatory synaptic channels (NR2B) that is known to cause cell damage and death. The function and expression of TRPM2 will be examined with aging, metabolic stress and in mouse models of Alzheimer's. The toxic interactions of TRPM2 and NR2B and their co-regulation will be studied. An agent that prevents this toxic action will be tested for potential benefits in preventing the degenerative changes underlying age-related degenerative diseases and Alzheimer's disease. We have identified a potential candidate drug for preventing such injury.
Schizophrenia is treated with drugs that inhibit one type of dopamine receptor in the brain and this help psychosis but fails help learning and memory deficits. A new concept is that there is a chronic reduction in the excitation between neurons. New drugs are being tried clinically to correct this deficit in synaptic transmission; and, they do so by targeting the NMDA receptor. We show that there are two different types of NMDA receptors in the hippocampus (a centre of learning and memory); and, each has very different effects on learning. We have found ways to selectively change the activity of each receptor subtype; and, to potentially use new drugs to restore the balance of activity between these receptors, rather than to arbitrarily boost NMDA, which can actually kill brain cells.
1975 PhD, Physiology and Neuroscience, University of British Columbia
1975 Medical Research Council of Canada, University of St. Andrews, United Kingdom
1976 Medical Research Council of Canada, McGill University, Montreal
1978 Fogarty International, National Institutes of Health, Bethesda, Maryland
Xie YF, Belrose JC, Lei G, Tymianski M, Mori Y, MacDonald JF, Jackson MF. Dependence of NMDA/GSK3beta Mediated Metaplasticity on TRPM2 Channels at Hippocampal CA3-CA1 Synapses. Mol Brain. 2011 Dec 21;4(1):44. [Epub ahead of print] PubMed PMID: 22188973.
Yang K, Trepanier C, Sidu B, Xie YF, Lei G, Li HB, Salter MW, Jackson MF, Orser, B.A., MacDonald JF Metaplasticity Gated through differential regulation of GluN2A versus GluN2B receptors by Src family kinases. EMBO J 2011 Dec 20. doi: 10.1038/emboj.2011.453. [Epub ahead of print] PubMed PMID: 22187052.
Li, H.B, Jackson, M.F. Yang, K. Trepanier, C, Salter, M.W., Orser, B.A. and MacDonald J.F. Plasticity of synaptic GluN receptors is required for the Src-dependent induction of LTP at CA3-CA1 synapses. Hippocampus, 2010 Jun 2. PMID: 20865743.
Loren Martin, Agnieska Zurek, John F. MacDonald, John Roder, Michael Jackson, and Beverley A. Orser. a5GABA receptor activity sets the threshold for long-term potentiation and constrains hippocampus-dependent memory. J. Neurosci. 2010 Apr 14;30(15):5269-82. PMID: 20392949.
Bartos JA, Ulrich JD, Li H, Beazely MA, Chen Y, Macdonald JF, Hell JW. Postsynaptic clustering and activation of Pyk2 by PSD-95. J Neurosci. 2010 Jan 13;30(2):449-63. PMID: 20071509.
Yang K, Lei G, Jackson MF, Macdonald JF. The involvement of PACAP/VIP system in the synaptic transmission in the hippocampus. J Mol Neurosci. 2010 Nov;42(3):319-26. PMID: 20414742.
Hong-Shuo Sun, Mike F. Jackson, Loren J Martin, Karen Jansen, Lucy Teves, Hong Cui, Shigeki Kiyonaka, Yasuo Mori, Michael Jones, Joan P. Forder, Todd E. Golde, Beverley A Orser, John F. MacDonald, Michael Tymianski. Suppression of hippocampal TRPM7 protein prevents delayed neuronal death in brain ischemia. Nature Neuroscience 2009; 12(10):1300-1307. PMID: 19734892.
Beazely MA, Lim A, Li H, Trepanier C, Chen X, Sidhu BR, Macdonald JF. Platelet-derived growth factor selectively inhibits NR2B-containing NMDA receptors in ca1 hippocampal neurons. J Biol Chem. 2008 Dec 23. PMID: 19106110.
Thompson RJ, Jackson MF, Olah ME, Rungta RL, Hines DJ, Beazely MA, MacDonald JF, MacVicar BA. Activation of pannexin-1 hemichannels augments aberrant bursting in the hippocampus. Science. 2008 Dec 5;322(5907):1555-9. PMID: 19056988.
Jindong Xu, Manjula Weerapura, Mohammad K. Ali, Michael F. Jackson, Gang Lei, Sheng Xue, Chun L. Kwan, Morris F. Manolson, John F. MacDonald and Xian-Min Yu. Control of Excitatory Synaptic Transmission by C-terminal Src Kinase. Journal of Biological Chemistry Jun 20;283(25):17503-14 2008. PMID: 18445593.
Dr. John MacDonald
Robarts Research Institute
100 Perth Drive
London, ON Canada N6A 5K8