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Paul Kotzbauer, MD, PhD

Our research is focused on Parkinson’s disease and a group of related neurodegenerative disorders caused by PLA2G6 gene mutations. Accumulation of aggregated alpha-synuclein protein within neuronal inclusions called Lewy bodies and Lewy neurites is the hallmark pathological change in Parkinson’s disease. A central role for alpha-synuclein in pathogenesis is supported by the previous identification of dominantly-inherited alpha-synuclein gene mutations in rare familial forms of PD. PD typically causes progressive motor impairment but also can cause cognitive impairment. Disease progression is associated with progressive involvement of cortical and subcortical brain regions with pathological alpha-syn accumulation.

PLA2G6 mutations are responsible for a spectrum of hereditary disorders classified as Neurodegeneration with brain iron accumulation (NBIA), infantile neuroaxonal dystrophy (INAD), and dystonia-parkinsonism. At the pathological level, PLA2G6 mutations cause alpha-synuclein accumulation in Lewy bodies and Lewy neurites, a feature shared with Parkinson’s disease. The PLA2G6 gene encodes an enzyme (Pla2g6) that catalyzes the hydrolysis of phospholipids and lysophospholipids to produce fatty acids. Disease-associated mutations impair the catalytic activity of the enzyme, leading to a deficiency of free fatty acid production. Approaches to reduce accumulation of Pla2g6 substrates or compensate for the deficiency of fatty acid production may have therapeutic value in addressing the consequences of impaired catalytic activity. Our Pla2g6-KO mouse model reproduces the progressive neurological impairment in the human disorder and is being utilized for further studies of disease mechanisms and therapeutic approaches.

Ongoing projects in the lab are investigating: 1) mechanisms underlying neurodegenerative disease progression including accumulation of aggregated protein, altered lipid metabolism, and changes in neurotransmitter levels, 2) the development of positron emission tomography (PET) radiotracers to measure aggregated alpha-synuclein in vivo, which could be used to monitor disease progression and 3) the development of therapeutic approaches for neurodegenerative disorders. We utilize a number of approaches including studies in mouse models and in vitro models for disease processes, as well as analyses of postmortem brain tissue and cerebrospinal fluid. These ongoing projects also involve collaborations with other labs that have expertise in chemistry, radiochemistry, and mouse behavioral analysis.

Medical Training

Dr. Kotzbauer graduated from Northwestern University in 1989 with a B.S. in Biomedical Engineering. He received his M.D. and Ph.D. degrees from Washington University School of Medicine in 1997. During his graduate work in the laboratory of Jeffrey Milbrandt M.D., Ph.D., he purified and cloned a novel peptide neurotrophic factor named neurturin which promotes the survival and growth of multiple neuronal populations, including dopaminergic neurons of the substantia nigra. He received the James L. O'Leary Prize for Research in Neuroscience for this work.

Dr. Kotzbauer completed an internship in the Department of Medicine at the University of Pennsylvania in 1998 and residency in the Department of Neurology at the University of Pennsylvania in 2001. He obtained further clinical training from 2001-2003 as a Movement Disorders fellow at the University of Pennsylvania under Matthew Stern M.D., and was a staff neurologist in the Parkinson's Disease Research Education and Clinical Center of the Philadelphia VA Medical Center from 2003-2005. He received a Howard Hughes Medical Institute Physician Postdoctoral Fellowship from 2001-2004 which supported postdoctoral research training in the Center for Neurodegenerative Disease Research headed by Virginia M.-Y. Lee at the University of Pennsylvania. In 2004, he was appointed Instructor in Neurology at the University of Pennsylvania.

In 2005, Dr. Kotzbauer joined the faculty of Washington University as an Assistant Professor in the Department of Neurology.

Selected Publications

Engel L.A., Jing Z., O’Brien D.E., Sun, M., Kotzbauer P.T. (2010). Catalytic Function of PLA2G6 is Impaired by Mutations Associated with Infantile Neuroaxonal Dystrophy but not Dystonia-Parkinsonism. PLoS ONE 5(9):e12897. PMCID: PMC2944820.

Gregory A., Westaway S.K., Holm I.E., Kotzbauer P.T., Hogarth P., Sonek S., Coryell J.C., Nguyen T.M., Nardocci N., Zorzi G., Rodriguez D., Desguerre I., Bertini E., Simonati A., Levinson B., Dias C., Barbot C., Carrilho I., Santos M., Malik I., Gitschier J., Hayflick S.J. (2009). Neurodegeneration associated with genetic defects in phospholipase A2. Neurology 71(18):1402-9. PMCID: PMC2676964

Malik, I., Turk, J., Mancuso, D.J., Montier, L., Wohltmann, M., Wozniak, D.F., Schmidt, R.E., Gross, R.W., Kotzbauer, P.T. (2008). Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations. The American Journal of Pathology 172(2):406-16. PMCID: PMC2312364

Kotzbauer, P.T., Truax, S., Trojanowski, J.Q., and Lee, V.M.-Y. (2005). Altered neuronal mitochondrial CoA synthesis in Neurodegeneration with brain iron accumulation (NBIA) due to abnormal processing, stability and catalytic activity of mutant PanK2. Journal of Neuroscience 25(3):689-98.

Kotzbauer, P.T., Giasson, B.I., Kravitz, A.V., Golbe, L.I., Mark, M.H., Trojanowski, J.Q., and Lee, V.M.-Y. (2004). Fibrillization of alpha-synuclein and tau in familial Parkinson’s disease caused by the A53T alpha-synuclein mutation. Experimental Neurology 187(2):279-88.

Giasson B.I., Forman M.S., Higuchi M., Golbe L.I., Graves C.L., Kotzbauer P.T., Trojanowski J.Q., Lee V.M-Y. (2003). Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 300(5619):636-40.

Kotzbauer, P.T., Lampe, P.A., Heuckeroth, R.O., Golden, J.P., Creedon, D.J., Johnson, E.M., Jr., Milbrandt, J. (1996). Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature 384: 467-470.

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