Debbie McKenzie

PhD: University of Calgary

Post-doctoral Physiological Chemistry, University of Wisconsin at Madison

Position: Professor

Department of Biological Sciences Faculty of Science

Centre for Prions and Protein folding diseases

E-mail: debbie.mckenzie@ualberta.ca

Background

My research interests encompass two major areas: prion disease and biology of aging. My interest in prion diseases has focused elucidating the properties of this unusual infectious agent as well as its biology and transmission properties. The major foci of my prion research are 1) etiological, biological and biochemical characterization of chronic wasting disease and 2) mechanisms of prion strain cell tropism. An additional focus of my laboratory is age-related changes in tissues defining the role of age-dependent accumulation of mitochondrial DNA deletion mutations on aging processes

Current Research

Chronic Wasting Disease (CWD) Strains:

CWD affects deer, elk, moose, and caribou across North America. We have demonstrated that polymorphisms in PRNP (the gene encoding the prion protein) affect susceptibility to disease and can result in the generation of novel strains. We recently described a new CWD strain, H95+ (Duque Velasquez et al., 2015). This novel strain has different biological (host range) and biochemical properties than more common cervid CWD strains. Ongoing studies include:

Characterization of CWD strains at the biological and biochemical levels.

Delineating interactions of CWD prions with soil and plants (Aiken, CPPFD),

Transcriptomic and proteomic analyses of CWD prion infections (Aiken, CPPFD, Stothard, UofA),

Biophysical analysis of CWD prions (Sim, CPPFD)

Structural analysis of CWD prions (Wille, CPPFD),

Analysis of CWD agents using conformation dependent immunoassay (Safar, Case Western Reserve University).

Transmission of CWD prions into cattle (tgbov mice, Cervenakova, American Red Cross) and humans (tgHu, Kong, Case Western Reserve University)

A recently funded Genome Canada project is using systems biology and molecular ecology approaches to characterizing CWD strains and developing tools to readily identify CWD in animals and the environment (11 co-investigators from UofA and U of Calgary).

Developing new cell lines susceptible to prion infection

Generation of novel cell lines expressing heterologous prion protein that are susceptible to human, cattle and deer prion strains.

Rapid screening of putative therapeutic agents,

Investigation of cell tropism for prion infection.

Innate Immune Responses and Prion Infection

Activation of innate immunity in primary cultures of mixed neuronal and glial cells results in a reduction of PrP-res accumulation (the misfolded conformer) while inhibition of specific immune pathways enhances prion accumulation (Kang et al., 2016). Ongoing studies involve elucidation of the role of clearance in prion disease pathogenesis.

Metabolic dysfunction in cells containing mitochondrial DNA deletions

The age-dependent loss of cells in the brain, muscle, heart and other terminally differentiated tissues is an integral component of the aging process, yet the molecular basis is not yet understood. We have, in collaboration with Aiken (CPPFD) and Wanagat (UCLA), demonstrated that age-dependent muscle fiber loss is a result of the accumulation of mitochondrial DNA deletion mutations. These deletion mutations occur focally and segmentally, cause abnormalities in the electron transport chain with subsequent fiber loss due to apoptotic and necrotic events (Cheema et al., 2015). Ongoing studies include the use of pharmacological interventions in the rat model to elucidate the underlying mechanisms of this accrual of mtDNA deletion-contain genomes leading to fiber loss.

Selected publications

Otero, A., Velásquez, C.D., Aiken, J. et al. Chronic wasting disease: a cervid prion infection looming to spillover. Vet Res 52, 115 (2021).

Otero A, Duque Velásquez C, Aiken J, McKenzie D. White-tailed deer S96 prion protein does not support stable in vitro propagation of most common CWD strains. Sci Rep. 2021 May 27;11(1):11193. doi: 10.1038/s41598-021-90606-8. PubMed PMID: 34045540; PubMed Central PMCID: PMC8160261.

Silva, C.J., M.L. Erickson-Beltran, C. Duque Velasquez, J.M. Aiken and D. McKenzie. 2019. A general mass spectrometry-based method of quantitating prion polymorphisms from heterozygous CWD-infected cervids. Analytical Chemistry. Dec 9. doi: 10.1021/acs.analchem.9b04449. [Epub ahead of print]

Herbst, A., A.N. Hoang, W. Woo, D. McKenzie, J.M. Aiken, R.A. Miller, D.B. Allison, N. Liu and J. Wanagat. Mitochondrial DNA alterations in aged macrophage migration inhibitory factor-knockout mice. Mechanisms in Ageing and Development. 82:111126. IF: 3.603. Ranking: (Aging) Q2.

Otero, A., C.D. Velasquez, C. Johnson, A. Herbst, R. Bolea, J.J. Badiola, J. Aiken and D. McKenzie. 2019. Prion protein polymorphisms associated with reduced CWD susceptibility limit peripheral PrPCWD deposition in orally infected white-tailed deer. BMC Veterinary Research 15: 50. IF: 1.98 Ranking: 20/140 (Veterinary Science) Q1.

Kuznetsova, A., C. Cullingham, D. McKenzie and J.M. Aiken. 2018. Soil humic acids degrade CWD prions and reduce infectivity. PLoS Pathogens 14: e1007414. IF: 6.158 Ranking: 14/126 (Microbiology) Q1.

Herbst, A., C.D. Velasquez, E. Triscott, J.M. Aiken and D. McKenzie. 2018. Chronic wasting disease prion protein strain emergence and host range expansion. Emerging Infectious Diseases 23: 1598-1600. IF: 7.422 Ranking: 4/88 (Infectious Disease) Q1.

Bielas, J., A. Herbst, K. Widjaja, J. Hui, J.M. Aiken, D. McKenzie, R.A. Miller, S.V. Brooks and J. Wanagat. 2018. Long term rapamycin treatment improves mitochondrial DNA quality in aging mice. Experimental Gerontology 106: 125-131. IF: 3.224 Ranking: 19/53 (Geriatics and Gerontology) Q2.

Herbst, A., K. Widjaja, B. Nguy, E.B. Lushaj, T.M. Moore, A.L. Hevener, D. McKenzie, J. Aiken and J. Wanagat. 2018. Digital PCR quantitation of muscle mitochondrial DNA: age, fiber type and mutation induced changes. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences 72: 1327-1333. IF: 4.902 Ranking: 7/53 (Geriatics and Gerontology) Q1.

Gushue, D., A. Herbst, V. Sim, D. McKenzie and J.M. Aiken. 2018. 14-3-3 and enolase abundances in the CSF of prion diseased rats. Prion 12: 253-260. IF: 2.011 Ranking: 209/293 (Biochemistry and Molecular Biology) Q3.

Kang, S.G., C. Kim, J. Aiken, H.S. Yoo and D. McKenzie. 2017. Dual microRNA to cellular prion protein inhibits propagation of pathogenic prion protein in cultured cells. Molecular Neurobiology 55: 2384-2396. IF: 5.076 Ranking: 44/261 (Neurosciences) Q1.