Paul T. Kotzbauer, M.D., Ph.D.
Molecular Cell Biology Program
124 Biotechnology Building
lipid metabolism, mouse models, neurodegeneration, pathogenesis, phospholipase A2, Parkinson disease
Mechanisms of neurodegeneration in Parkinson`s disease and related disorders
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 proximal 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 analyses of postmortem brain tissue and cerebrospinal fluid, which are combined with studies in mouse models and in vitro models for disease processes.
Kotzbauer, P.T., Cairns, N.J., Campbell, M.C., Willis, A.W., Racette, B.A., Tabbal, S.D., Perlmutter, J.S.. Pathological Accumulation of α-Synuclein and Aβ in Dementia Associated with Parkinson Disease. Archives of Neurology 2012 Jul 23:1-6. doi: 10.1001/archneurol.2012.1608. [Epub ahead of print]
Yu L, Cui J, Padakanti PK, Engel L, Bagchi DP, Kotzbauer PT, Tu Z. Synthesis and in vitro evaluation of α-synuclein ligands. Bioorganic and Medicinal Chemistry 2012 20(15):4625-34.
Engel LA, Jing Z, O’Brien DE, Sun M, Kotzbauer PT. Catalytic Function of PLA2G6 is Impaired by Mutations Associated with Infantile Neuroaxonal Dystrophy but not Dystonia-Parkinsonism. PLoS ONE 2010 5(9):e12897. PMCID: PMC2944820.
Gregory A, Westaway SK, Holm IE, Kotzbauer PT, Hogarth P, Sonek S, Coryell JC, Nguyen TM, 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 SJ. Neurodegeneration associated with genetic defects in phospholipase A2. Neurology 2009 71(18):1402-9. PMCID: PMC2676964
Malik I, Turk J, Mancuso DJ, Montier L, Wohltmann M, Wozniak DF, Schmidt RE, Gross RW, Kotzbauer PT. 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 2008 172(2):406-16. PMCID: PMC2312364
Kotzbauer PT, Truax S, Trojanowski JQ and Lee VM-Y. 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 2005 25(3):689-98.
Kotzbauer PT, Giasson BI, Kravitz AV, Golbe LI, Mark MH, Trojanowski JQ and Lee VM-Y. Fibrillization of alpha-synuclein and tau in familial Parkinson’s disease caused by the A53T alpha-synuclein mutation. Experimental Neurology 2004 187(2):279-88.
Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VM-Y. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 2003 300(5619):636-40.
Kotzbauer PT, Lampe PA, Heuckeroth RO, Golden JP, Creedon DJ, Johnson, Jr. EM, Milbrandt J. Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature 1996 384: 467-470.
Last Updated: 9/4/2012 9:11:27 AM