Research Statement

Dr. McManus' fascination with mitochondria began as a biochemistry and molecular biology major at the University of Georgia, and she hs been infatuated ever since. Her undergraduate and graduate course work provided the background needed to decipher key biochemical pathways dictating pathognomonic events, and how to use this knowledge to isolate the most promising molecular target for therapeutic success. As such, she began investigating the relationship between mitochondrial dysfunction and neuronal demise under the guidance of James Franklin, Ph.D. She was then inspired to work with Michael Murphy, Ph.D., on the development of mitochondria-targeted antioxidants as a neuroprotective strategy for Alzheimer’s disease (AD). Their studies were the first to prove mitochondria-targeted therapeutics could prevent the onset and progression of AD in animal models. 
Dr. McManus' work to date has left her increasingly convinced that correcting and preserving mitochondrial integrity is the only way we will truly modify the progression of age-related disorders, especially those of the brain. This hypothesis led her to Doug Wallace and the excitement hasn’t stopped since. Her adventures at CMEM revolve around the complex interplay between mitochondrial genetics, energetics, epigenetics, and the environment. Dr. McManus' primary goal is to prove the etiological significance of mitochondrial DNA (mtDNA) variation in the progression of neurodegenerative disease.  She is currently investigating the impact of mtDNA mutations on cognition and behavior, mitophagy, inflammation, and neurological demise.  Her second major project focuses on the interaction between nuclear and mitochondrial DNA in the development of mitochondrial cardiomyopathy. Using several genetic combinations, our preliminary results suggest mtDNA mutations increase the penetrance of cardiomyopathy caused by deficiency in the nDNA-encoded adenine nucleotide translocator (ANT1).

Selected Publications

• Sharpley, M, Marciniak, C, Eckel-Mahan K, McManus M, Crimi, M, Lin, C,  Masubuchi S, Waymire, K, Friend, N, Koike, M, MacGregor, G, Sassone-Corsi, P, and Douglas C. Wallace. 2012. Heteroplasmy of mouse mtDNA is genetically unstable and results in altered behavior and cognition. Cell, Oct 12; 151 (2): 333-43.
• Chun S.L., Sharpley, M.S., Fan, W., Waymire, K.G.,  Sadun,  A., Carelli,V., Ross-Cisneros F.N., Baciu, P., Sung, E.,  McManus M.J., Pan, B.J., Gil, D.W., MacGregor, G.R., and Douglas C. Wallace. 2012.  A Mouse mtDNA Mutant Model of Leber’s Hereditary Optic Neuropathy. PNAS, Proc Natl Acad Sci U S A. 2012 Dec 4; 109 (49): 20065-70.
• McManus MJ, Murphy MP, Franklin JL. 2011. The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer's disease. J Neurosci. 31(44):15703-15.

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