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

Dziarmaga, A., P.A. Hueber, D. Iglesias, N. Hache, A. Jeffs, N. Gendron, A.E. MacKenzie, M. Eccles, and P. Goodyer (2006).  Neuronal apoptosis inhibitory protein is expressed in developing kidney and is regulated by PAX2.  Am J Physiol Renal Physiol, 291:F913-20.

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.

Yin, Y., W.W. Huang, C. Lin, H. Chen, A. MacKenzie, and L. Ma (2007).  Estrogen suppresses uterine epithelial apoptosis by inducing Birc1 expression.  Mol Endocrinology, Sept 27.

Davoodi, J., A. Mohammad-Gholi, A. Es-Haghi, and A. MacKenzie(2007).  W323S variant of Xiap-Bir3 binds to SMAC but not caspase-9.  J Biochem (Tokyo), 141:293-9.

Ting, J.P., R.C. Lovering, E.S. Alnemri, J. Bertin, J.M. Boss, B.K. Davis, R.A. Flavell, S.E. Girardin, Z. Godzik, J.A. Harton, H.M. Hoffman, J.P. Hugot, R. Inohara, A. MacKenzie, L.J. Maltais, G. Nunez, Y. Ogura, L.A. Otten, D. Philpott, J.C. Reed, W. Reith, S. Schreiber, V. Steimle, and P.A. Ward (2008).  The NLR gene family:  a standard nomenclature.  Immunity, 28:285-7.

Shafey, D., A.E. MacKenzie, and R. Kothary (2008).  Neurodevelopmental abnormalities in neurosphere-derived neural stem cells from SMN-depleted mice.  J Neurosci Res, 86:2839-47.

Arbour, N., J.L. Vanderluit, J.N. Le Grand, A. Jahani-Asl, V.A. Ruzhynsky, E.C. Cheung, M.A. Kelly, A.E. MacKenzie, D.S. Park, J.T. Opferman, and R.S. Slack (2008).  Mcl-l is a key regulator of apoptosis during CNS development and after DNA damage.  J Neurosci 28:6068-78.

Nguyen, T.M., E. Humphrey, L.T. Lam, H.R. Fuller, T.A. Lynch, C.A. Sewry, P.R. Goodwin, A.E. MacKenzie, G.E. Morris (2008).  A two-site ELISA can quantify upregulation of SMN protein by drugs for spinal muscular atrophy.  Neurology 71:1752-3.

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)

Laboratory Personnel

• Graduate Student - Faraz Farooq

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