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
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.
Herbst, A., J. Wanagat, N. Cheema, K. Widjaja, D. McKenzie and J.M. Aiken. (2016). Latent mitochondrial DNA deletion mutations drive muscle fiber loss at old age. Aging Cell.
Kang S.G. , C. Kim, L.M. Cortez, M. Carmen Garza, J. Yang, H. Wille, V.L Sim, D. Westaway, D. McKenzie and J. Aiken. (2016). Toll-like receptor-mediated immune response inhibits prion propagation.Glia.. 64(6):937-51.
Herbst, A., A. Ness, C.J. Johnson, D. McKenzie and J. Aiken. (2015). Transcriptomic approaches to prion disease in rats. BMC Genomics.16: 682.
Wolf, H., A. Hossinger, A. Fehlinger, S. Buttner, V. Sim, D. McKenzie and I.M. Vorberg. (2015). Deposition pattern and subcellular distribution of disease-associated prion protein in cerebellar organotypic slice cultures infected with scrapie.. Frontiers in Neuroscience 9:410.
Cheema, N., A. Herbst, D. McKenzie and J. Aiken. (2015). Apoptosis and necrosis in aged skeletal muscle fibers with mitochondrial enzyme abnormalities induces fiber atrophy and loss, Aging Cell 14:1085-93.