The candidate is an M.D./Ph.D neurologist who is currently a trainee in the Center for Neurodegenerative Disease Research. His goal is to develop additional research skills and experience needed to become an independent clinician scientist working to understand the pathogenesis of neurodegenerative diseases. The proposed research project focuses on neurodegeneration with brain iron accumulation (NBIA), which causes progressive impairment of speech, movement and cognition. At the neuropathological level, NBIA is characterized by iron accumulation, inclusion formation, signs of oxidative stress, and death of multiple neuronal populations. These features are also seen to varying degrees in other neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Mutations in the gene for pantothenate kinase 2 (PanK2) were recently identified in a subset of NBIA cases. The PanK2 gene encodes an enzyme involved in coenzyme A (CoA) synthesis, a critical pathway linked to a number of cellular processes, including fatty acid synthesis, energy production, and possibly, synthesis of anti-oxidant molecules. The long term objectives of this project are to understand how PanK2 mutations lead to iron accumulation, oxidative stress, inclusion formation, and neuronal death. The proteolytic processing, mitochondrial localization and in vitro catalytic properties will by characterized for mutant Pank2 proteins and compared to the wild type human PanK2 protein. Cell culture systems will be established in which PanK2 expression is eliminated and in which wild type or mutant PanK2 proteins are over-expressed. Mice that lack PanK2 expression will also be generated. Cell lines and mice lacking PanK2 expression will be examined for changes in levels of biochemical intermediates hypothesized to be dependent on PanK2 function. Finally, neuronal and non-neuronal cells lacking PanK2 will be examined for signs of increased oxidative stress, susceptibility to oxidative injury, cellular and mitochondrial import of radio labeled iron, and inclusion formation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08NS048924-05
Application #
7216264
Study Section
NST-2 Subcommittee (NST)
Program Officer
Murphy, Diane
Project Start
2004-08-15
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
5
Fiscal Year
2007
Total Cost
$176,002
Indirect Cost
Name
Washington University
Department
Neurology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Dhavale, Dhruva D; Tsai, Christina; Bagchi, Devika P et al. (2017) A sensitive assay reveals structural requirements for ?-synuclein fibril growth. J Biol Chem 292:9034-9050
Campbell, Meghan C; Koller, Jonathan M; Snyder, Abraham Z et al. (2015) CSF proteins and resting-state functional connectivity in Parkinson disease. Neurology 84:2413-21
Lucero, Carolyn; Campbell, Meghan C; Flores, Hubert et al. (2015) Cognitive reserve and ?-amyloid pathology in Parkinson disease. Parkinsonism Relat Disord 21:899-904
Buddhala, Chandana; Campbell, Meghan C; Perlmutter, Joel S et al. (2015) Correlation between decreased CSF ?-synuclein and A????? in Parkinson disease. Neurobiol Aging 36:476-84
Campbell, Meghan C; Markham, Joanne; Flores, Hubert et al. (2013) Principal component analysis of PiB distribution in Parkinson and Alzheimer diseases. Neurology 81:520-7
Kotzbauer, Paul T; Cairns, Nigel J; Campbell, Meghan C et al. (2012) Pathologic accumulation of ?-synuclein and A? in Parkinson disease patients with dementia. Arch Neurol 69:1326-31
Engel, Laura A; Jing, Zheng; O'Brien, Daniel E et al. (2010) Catalytic function of PLA2G6 is impaired by mutations associated with infantile neuroaxonal dystrophy but not dystonia-parkinsonism. PLoS One 5:e12897
Mancuso, David J; Kotzbauer, Paul; Wozniak, David F et al. (2009) Genetic ablation of calcium-independent phospholipase A2{gamma} leads to alterations in hippocampal cardiolipin content and molecular species distribution, mitochondrial degeneration, autophagy, and cognitive dysfunction. J Biol Chem 284:35632-44
Malik, Ibrahim; Turk, John; Mancuso, David J et al. (2008) Disrupted membrane homeostasis and accumulation of ubiquitinated proteins in a mouse model of infantile neuroaxonal dystrophy caused by PLA2G6 mutations. Am J Pathol 172:406-16