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Parkinson's disease and related disorders
We are working to understand mechanisms of neurodegeneration underlying Parkinson’s disease and related disorders.   Specific types of pathological neuronal inclusions that occur in Parkinson’s disease also occur in other neurodegenerative diseases, suggesting that common mechanisms of pathogenesis may be involved.  Of particular interest are rare familial disorders resulting from recently identified gene mutations.  By studying the consequences of these gene mutations and their relationship to observed pathological changes in the brain, we hope to understand mechanisms potentially relevant to a number of disorders.

Dominant mutations in the gene for alpha-synuclein cause a rare familial form of Parkinson’s disease.  The alpha-synuclein protein is a primary structural component of Lewy bodies and other pathological inclusions found in non-familial Parkinson’s disease.  The deposition of alpha-synuclein in both familial and sporadic diseases involves fibrillization, a specific structural alteration that leads to the formation of insoluble filaments. Using cell culture and animal models, we are investigating conditions that promote or deter inclusion formation and the effect of alpha-synuclein on neuronal metabolism.

Mutations in the pantothenate kinase 2 (PANK2) gene were recently identified in neurodegeneration with brain iron accumulation (NBIA), a rare progressive neurodegenerative disorder that often begins in childhood and affects multiple brain areas including basal ganglia and cortex.  Neurodegeneration in this disorder is accompanied by alpha-synuclein positive inclusions similar to Parkinson’s disease as well as tau positive inclusions similar to Alzheimer’s disease. The PanK2 protein catalyzes the initial step in coenzyme A synthesis, but unlike other pantothenate kinases, PanK2 is localized to neuronal mitochondria.  Our studies suggest that PanK2 may regulate neuronal mitochondrial lipid metabolism.  We are using cell culture and transgenic mouse systems to study the consequences of PanK2 loss of function and its relationship to inclusion formation, which may provide insight into altered neuronal metabolism underlying NBIA as well as other neurodegenerative diseases.


Research Publications

Kotzbauer PT, Truax AC, Trojanowski JQ, Lee VM (2005 Jan 19). Altered neuronal mitochondrial coenzyme A synthesis in neurodegeneration with brain iron accumulation caused by abnormal processing, stability, and catalytic activity of mutant pantothenate kinase 2. J Neurosci. 25 (3): 689-98. Full Article >

Kotzbauer PT, Giasson BI, Kravitz AV, Golbe LI, Mark MH, Trojanowski JQ, Lee VM (2004 Jun). Fibrillization of alpha-synuclein and tau in familial Parkinson's disease caused by the A53T alpha-synuclein mutation. Exp Neurol. 187 (2): 279-88. Full Article >

Giasson BI, Forman MS, Higuchi M, Golbe LI, Graves CL, Kotzbauer PT, Trojanowski JQ, Lee VM (2003 Apr 25). Initiation and synergistic fibrillization of tau and alpha-synuclein. Science. 300 (5619): 636-40. Full Article >

Kotzbauer PT, Trojanowsk JQ, Lee VM (2001 Oct). Lewy body pathology in Alzheimer's disease. J Mol Neurosci. 17 (2): 225-32. Full Article >

Contact Info
Paul Kotzbauer, M.D., Ph.D.
Office Location: 115 Biotechnology Bldg
Office Phone: 314-362-7165
Lab Phone: 314-362-7193
Campus Box: 8111
Fax: 314-362-2244

kotzbauerp@neuro.wustl.edu