Research Abstract:
Our research is focused on mechanisms of neurodegeneration underlying Parkinson’s disease and related 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 pathological intracellular inclusions found in both familial and sporadic forms of Parkinson’s disease. The deposition of alpha-synuclein in these 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 the accumulation of misfolded protein 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.
Selected Publications:
Liang T-W, Truax AC, Trojanowski JQ, et al. Partial deficit of pantothenate kinase 2 catalytic activity in a case of tremor-predominant neurodegeneration with brain iron accumulation. Movement Disorders 2006 (in press).
Kotzbauer PT, Truax AC, Trojanowski JQ, 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. J Neurosci 2005 25:689-98.
Kotzbauer PT, Giasson BI, Kravitz AV, et al. Fibrillization of alpha-synuclein and tau in familial Parkinson’s disease caused by the A53T alpha-synuclein mutation. Exp Neurol 2004 187:279-88.
Giasson BI, Forman MS, Higuchi M, et al. Initiation and synergistic fibrillization of tau and alpha-synuclein. Science 2003 300:636-40.
Kotzbauer PT, Lampe PA, Heuckeroth RO, et al. Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature 1996 384:467-470.
Last Updated: 12/21/2006 |