Biology and Etiology of Prions:
Prion diseases are slowly progressive, fatal neurodegenerative disorders with no effective treatment or vaccine available. Neuropathological changes include accumulation of abnormal prion protein aggregates, spongiform degeneration, neuronal loss and astrogliosis. These hallmarks are diagnostic for chronic wasting disease (CWD) in cervids as well as scrapie in sheep and goats, bovine spongiform encephalopathy (BSE) as well as Creutzfeld-Jakob disease (CJD) and variant CJD in humans. This research program has two primary areas of interest: i) Understanding the role of environmental contamination including the binding of shed CWD prions to soils and plants in the transmission of CWD in cervid populations (soil can serve as a stable reservoir for infectious prion proteins; prions bound to soil particles remain infectious in the soils for many years) and, ii) Developing “omics” approaches to biomarker development to provide insights to the pathology and etiology of prion disease.
Mitochondrial DNA (mtDNA) mutations cause muscle fiber loss with age:
The loss of muscle mass and function with age is an inevitable component of the aging process. In humans, skeletal muscle fiber number in quadriceps declines from 600,000 at 50 years of age to 323,000 at 80 years. We have demonstrated that one cause of this decline in fiber number is the accumulation of mtDNA genomes containing large deletion mutations. Our studies suggest a progression of events beginning with the generation and accumulation of a mtDNA deletion mutation, the concomitant development of electron transport chain, a subsequent triggering of apoptotic and necrotic events, a process resulting in muscle fiber atrophy, breakage, and ultimately fiber loss.
Environmental Contamination by Prions:CWD is expanding both in terms of its geographic range; currently present in 24 US states, 2 Canadian provinces (Saskatchewan and Alberta), South Korea and Norway. Unlike other prion diseases, CWD affects free-ranging populations of deer, elk, moose and reindeer. Infected animals shed infectious agent in their saliva, urine, feces as well as from decaying carcasses. These prions in the environment are stable and can bind to both soil and plants. We are interested in determining the persistence and bioavailability of prions shed into the environment and developing methods to readily detect environmental CWD contamination.
An “omics” approach to Prion Biology:We are using a combination of genomic, transcriptomic and proteomic approaches to identifying biomarkers of prion disease in laboratory models of disease as well as in humans and deer. These biomarkers will direct studies into the pathobiology of prion disease allowing us to determine critical pathways in disease. A long-term goal is to develop diagnostics with high sensitivity and specificity for prion disease, particularly for
MtDNA deletion mutations and Aging: We employ a variety of state-or-the-art molecular and histological methodologies to elucidate the mechanisms involved in age-dependent muscle fiber loss. Our studies also examine the accumulation and impact of mtDNA deletion mutations in aged cardiac and brain tissue. Using pharmacological interventions, we have been investigating the underlying mechanism driving the increase in mtDNA deletion mutations with age and the concomitant loss of electron transport activity and ultimately fiber loss.
Selected publicationsHerbst, 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). 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.
Duque-Velasquez, C., C. Kim, A. Herbst, N. Daude, M.C. Garza, H. Wille, J.M. Aiken and D. McKenzie. (2015). Deer prion Protein allotypes modulate the transmissibility of Chronic Wasting Disease. Journal of Virology. 89: 12362-73.
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.