Scientific Centres

Alex MacKenzie, M.D. Ph.D.
Chief Executive Officer and Scientific Director, Children's Hospital of

Tel: (613) 737-2772
Fax: (613) 738-4833
E-mail

Biographical Sketch

Alex MacKenzie trained at the University of Ottawa (B.Sc., 1976, Pediatric Licensure, 1988) and University of Toronto (M.D., 1984, Ph.D. 1986). A professor in the Department of Pediatrics at the University of Ottawa and attending physician at the Children’s Hospital of Eastern Ontario, he studies inherited pediatric illnesses, with a particular focus on the neurodegenerative disorder, spinal muscular atrophy. In his spare time he twitches, fidgets and listens to excruciating country music.

Research Interests

Spinal Muscular Atrophy
I am interested mainly in the study of Spinal Muscular Atrophy (SMAs). The childhood spinal muscular atrophies (SMAs) are fatal autosomal recessive neurodegenerative diseases characterized by the loss of the alpha-motor neurons of the spinal cord. The SMA region of human chromosome 5q13 contains two copies of the SMN gene (the SMA causative SMN1 gene as well as the highly homologous SMN2) in addition to copies of the Neuronal Apoptotic Inhibitory Protein (NAIP). Type I SMA is the most severe form of the disease with an onset either in utero or immediately post-natally and survival only rarely beyond the first two years of life. The SMN1 gene is homozygously deleted in 95% of SMA cases. Deletions of the contiguous NAIP gene, observed in about two thirds of the most severe SMA, is also believed to modify SMA severity. My laboratory works on various aspects of the disease:

SMA therapeutics. A key goal is the establishment of a drug screening assay for SMN2 induction. In collaboration with the biotech company Virtek, we are now involved in the development of a fiber optic nucleic acid (FONA) biosensor based search for small molecules that induce SMN2. In addition to the identification of potential drugs for the treatment of SMA, the goals for the technology include screening of newborns for SMA as well as the eventual screening of patients for other genetic diseases. (www.virtekvision.com/releases/pdf/040902.pdf; www.uottawa.ca/services/markcom/gazette/ 021213/021213-art1-e.html)

Motor neuron profiling in mouse models of SMA. Using various SMA mouse models we are investigating how the depletion of the SMN protein exclusively affects motor neurons, when SMN is ubiquitously expressed and required in all cells. Extensive profiling of RNA expression, protein expression and signaling pathways in young mice affected with mild SMA has shown a number of changes, at an age that precedes any cellular attrition or clinical features.

Neuronal Apoptosis Inhibitory Protein
Role of NAIP in SMA. NAIP is both transcribed and translated in the motor neuron and encodes an anti-apoptotic protein. Our laboratory explores the role of NAIP in SMA as well as its potential therapeutic value for this disease. We have generated a number of NAIP transgenic mouse models with an SMA background, and are assessing the changes in phenotype wrought by the overexpression of NAIP. We are also collaborating with the Molecular Genetics Diagnostic Laboratory of CHEO to asses the value of NAIP as a phenotypic modifier in SMA patients.

Investigation of the neuroprotective role of NAIP in other models of neurodegeneration. In collaboration with scientists at CHEO and McMaster University, we are studying the mechanism of NAIP protection both in traumatic brain injury and in retinal degeneration models.

NAIP function, regulation, and interaction: NAIP belongs to a large family of Inhibitor of Apoptosis proteins. Although all members of the family have the same caspase inhibitory role, they demonstrate a variety of sites of action as well as additional roles and regulation pathways. We are investigating the specific pathways for NAIP regulation, as well as the delineation of NAIP interacting partners and their roles.

Selected publications

Roy, N., M.S. Mahadevan, M. McLean, G. Shutler, Z. Yaraghi, R. Farahani, S. Baird, A. Besner-Johnston, C. Lefebvre, X. Kang, M. Salih, H. Aubry, K. Tamai, X.P. Guan, P. Ioannou, T.O. Crawford, P. de Jong, L. Surh, J-E Ikeda, R.G. Korneluk and A.E. MacKenzie (1995).  The gene for neuronal apoptosis inhibitory protein (NAIP), a novel protein with homology to baculoviral inhibitors of apoptosis, is partially deleted in individuals with Type I, II and III SMA.  Cell 80:167-178.

Roy, N. M.D. McLean, A. Besner-Johnston, C. Lefebvre, M. Salih, Z. Yaraghi, J-E Ikeda, R.G. Korneluk, and A.E. MacKenzie (1995).  Refined physical map of the spinal muscular atrophy gene (SMA) region at 5q13 based on YAC and cosmid contiguous arrays.  Genomics 26:451-460.

Yaraghi, Z., McLean, M. D., Roy, N., Surh, L., Ikeda, J. E., Korneluk, R. G., and MacKenzie, A. (1995). A recombination event occurring within two complex 5q13.1 microsatellite repeat polymorphisms suggests a telomeric mapping of spinal muscular atrophy. Hum Genet 96, 330-334.

Chen, Q., Neville, C., MacKenzie, A., and Korneluk, R. G. (1996). Automated DNA sequencing requiring no DNA template purification. Biotechniques 21, 453-457.

Hughes-Benzie, R. M., Pilia, G., Xuan, J. Y., Hunter, A. G., Chen, E., Golabi, M., Hurst, J. A., Kobori, J., Marymee, K., Pagon, R. A., H.H. Punnett, S. Schelley, J.L. Tolmie, M.M. Wohlferd, T. Grossman, D. Schlessinger, and A.E. MacKenzie (1996). Simpson-Golabi-Behmel syndrome: genotype/phenotype analysis of 18 affected males from 7 unrelated families. Am J Med Genet 66, 227-234.

Liston, P., N. Roy, K. Tamai, C. Lefebvre, S. Baird, G. Cherton-Horvat, R. Farahani, M. McLean, J-E Ikeda, A.E. MacKenzie and R.G. Korneluk (1996).  Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes.  Nature 379:349-353.

Pilia, G., R.M. Hughes-Benzie, A.E. MacKenzie, P. Baybayan, E.Y. Chen, R. Huber, G. Neri, A. Cao, A. Forabosco and D. Schlessinger (1996).  Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome.  Nature Genet. 12(3):241-247.

Rajcan-Separovic, E., Mahadevan, M. S., Lefebvre, C., Besner-Johnston, A., Ikeda, J. E., Korneluk, R. G., and MacKenzie, A. (1996). FISH detection of chromosome polymorphism and deletions in the spinal muscular atrophy (SMA) region of 5q13. Cytogenet Cell Genet 75, 243-247.

Farahani, R., Fong, W. G., Korneluk, R. G., and MacKenzie, A. E. (1997). Genomic organization and primary characterization of miap-3: the murine homologue of human X-linked IAP. Genomics 42, 514-518.

Xu, D. G., Crocker, S. J., Doucet, J. P., St-Jean, M., Tamai, K., Hakim, A. M., Ikeda, J. E., Liston, P., Thompson, C. S., Korneluk, R. G., A. MacKenzie, and G.S. Robertson. (1997). Elevation of neuronal expression of NAIP reduces ischemic damage in the rat hippocampus. Nat Med 3, 997-1004.

Chen, Q., Baird, S. D., Mahadevan, M., Besner-Johnston, A., Farahani, R., Xuan, J., Kang, X., Lefebvre, C., Ikeda, J. E., Korneluk, R. G., and MacKenzie, A. E. (1998). Sequence of a 131-kb region of 5q13.1 containing the spinal muscular atrophy candidate genes SMN and NAIP. Genomics 48, 121-127.

LaCasse, E. C., Baird, S., Korneluk, R. G., and MacKenzie, A. E. (1998). The inhibitors of apoptosis (IAPs) and their emerging role in cancer. Oncogene 17, 3247-3259.

Yaraghi, Z., Korneluk, R. G., and MacKenzie, A. (1998). Cloning and characterization of the multiple murine homologues of NAIP (neuronal apoptosis inhibitory protein). Genomics 51, 107-113.

Gendron, N. H., and MacKenzie, A. E. (1999). Spinal muscular atrophy: molecular pathophysiology. Curr Opin Neurol 12, 137-142.

Xuan, J. Y., Hughes-Benzie, R. M., and MacKenzie, A. E. (1999). A small interstitial deletion in the GPC3 gene causes Simpson-Golabi-Behmel syndrome in a Dutch-Canadian family. J Med Genet 36, 57-58.

Yaraghi, Z., Diez, E., Gros, P., and MacKenzie, A. (1999). cDNA cloning and the 5'genomic organization of Naip2, a candidate gene for murine Legionella resistance. Mamm Genome 10, 761-763.

Diez, E., Yaraghi, Z., MacKenzie, A., and Gros, P. (2000). The neuronal apoptosis inhibitory protein (Naip) is expressed in macrophages and is modulated after phagocytosis and during intracellular infection with Legionella pneumophila. J Immunol 164, 1470-1477.

Holcik, M., Thompson, C. S., Yaraghi, Z., Lefebvre, C. A., MacKenzie, A. E., and Korneluk, R. G. (2000). The hippocampal neurons of neuronal apoptosis inhibitory protein 1 (NAIP1)-deleted mice display increased vulnerability to kainic acid-induced injury. Proc Natl Acad Sci U S A 97, 2286-2290.

MacKenzie, A. (2000). Mouse models for spinal muscular atrophy. Pediatr Res 48, 2.

MacKenzie, A., and LaCasse, E. (2000). Inhibition of IAP's protection by Diablo/Smac: new therapeutic opportunities? Cell Death Differ 7, 866-867.

Hutchison, J. S., Derrane, R. E., Johnston, D. L., Gendron, N., Barnes, D., Fliss, H., King, W. J., Rasquinha, I., MacManus, J., Robertson, G. S., and MacKenzie, A. E. (2001). Neuronal apoptosis inhibitory protein expression after traumatic brain injury in the mouse. J Neurotrauma 18, 1333-1347.

MacKenzie, A. E., and Gendron, N. H. (2001). Tudor reign. Nat Struct Biol 8, 13-15.

Ingram-Crooks, J., Holcik, M., Drmanic, S., and MacKenzie, A. E. (2002). Distinct expression of neuronal apoptosis inhibitory protein (NAIP) during murine development. Neuroreport 13, 397-402.

Maier, J. K., Lahoua, Z., Gendron, N. H., Fetni, R., Johnston, A., Davoodi, J., Rasper, D., Roy, S., Slack, R. S., Nicholson, D. W., and MacKenzie, A. E. (2002). The neuronal apoptosis inhibitory protein is a direct inhibitor of caspases 3 and 7. J Neurosci 22, 2035-2043.

Watterson, J.H., Raha, S., Kotoris, C.C., Wust, C.C., Gharabaghi, F., Jantzi, S.C., Haynes, N.K., Gendron, N.H., Krull, U.J., MacKenzie, A.E., and Piunno, P.A.E. (2004).  Rapid detection of SNPs using a reusable fiber-optic biosensor.  Nucleic Acid Research 23:32(2).

Davoodi, J., L. Lin, J. Kelly, P. Liston, and A.E. MacKenzie (2004).  Neuronal apoptosis inhibitory protein does not interact with Smac and requires ATP to bind caspase-9.  Journal of Biol Chemistry, 279:40622-8.

Davoodi, J., A. Mohammad-Gholi, A. Es-Haghi, and A.E. MacKenzie (2006).  W323S variant of XIAP-Bir3 binds to SMAC but not caspase-9.  J Biochem 141:293-9.

Mikrogianakis, A., R.E. Shaye, P. Griffin, S. Kawesa, J. Lockwood, N.H. Gendron, I. Gaboury, Z. Merali, A.E. MacKenzie, and J.S. Hutchison (2007).  Hypoxia alters the expression of inhibitor of apoptosis proteins after brain trauma in the mouse.  J Neurotrauma, 24:338-53.

Balabanian, S., N.H. Gendron, and A.E. MacKenzie (2007).  Histologic and transcriptional assessment of a mild SMA model.  Neurol Res., 29:413-24.

Davoodi, J., J. Kelly, N. Gendron, and A.E. MacKenzie (2007).  The Simpson-Golabi-Behmel syndrome causative Glypican-3, binds to and inhibits the dipeptidyl peptidase activity of CD26.  Proteomics 7:2300-10.

Maier, J.K.X., S. Balabanian, C.R. Coffill, A. Stewart, L. Pelletier, D.J. Franks, N.H. Gendron, and A.E. MacKenzie (2007).   The distribution of neuronal apoptosis inhibitory protein in human tissues.   Journal of Histochemistry & Cytochemistry 55:911 23.

Major Awards/Affiliations

• Scientist of the Year Award (Muscular Dystrophy Association of Canada) (1999)
• Burroughs Wellcome Clinical Translational Award (1998)
• Medical Research Council Scientist Award (1996)
• Ottawa Life Sciences Applied Research Award (Shared with Dr. Robert G. Korneluk) (1995)
• University of Ottawa Faculty of Medicine Award of Excellence (1995)
• Currently receiving funding from the Canadian Institute of Health Research,
• The Burroughs Wellcome Foundation Genome Canada, Families of Spinal Muscular Atrophy, Andrew’s Buddies and l’Association Française contre les Myopathies.

Laboratory Personnel

• Technician - Lucie Hyde

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