Many degenerative neurologic disorders appear to have a primary basis in mitochondrial dysfunction and more specifically in dysfunction of the electron transport chain. Because of the non- Mendelian genetics of some of the electron transport chain proteins which are inherited on the mitochondrial genome, the pattern of inheritance of some of these disorders such as kearns- Sayre syndrome (KSS), and some of the """"""""mitochondrial myopathies"""""""" has been difficult to analyze. In fact, some of these disorders have been considered sporadic rather than genetic. Study of these disorders has been severely hampered by the extreme difficulty encountered in obtaining adequate amounts of mitochondria. We have recently developed a method for purifying previously unobtainable amounts of human mitochondria (25-40 mg mitochondrial protein) from patient platelets collected by plateletpheresis. Using this method we have been able to employ standard but previously unusable biochemical methods. We will study patient mitochondria using standard catalytic assays, inhibitor titrations, aborbance and electron paramagnetic resonance spectroscopy, and ultimately immunologic methods. These approaches will define catalytic deficiencies resulting from mutations in proteins containing redox prosthetic groups and those that do not but which are required for electron transport of assembly of redox complexes. This project will lead both to a better understanding of the disorders studied and to a more general understanding of mitochondrial genetics and their influence on the brain.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS025382-05
Application #
3410672
Study Section
Physical Biochemistry Study Section (PB)
Project Start
1988-02-01
Project End
1993-06-30
Budget Start
1992-02-01
Budget End
1993-06-30
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Type
Schools of Medicine
DUNS #
065391526
City
Aurora
State
CO
Country
United States
Zip Code
80045
Swerdlow, R H; Parks, J K; Miller, S W et al. (1996) Origin and functional consequences of the complex I defect in Parkinson's disease. Ann Neurol 40:663-71
Howell, N; Kubacka, I; Smith, R et al. (1996) Association of the mitochondrial 8344 MERRF mutation with maternally inherited spinocerebellar degeneration and Leigh disease. Neurology 46:219-22
Parker Jr, W D; Parks, J; Filley, C M et al. (1994) Electron transport chain defects in Alzheimer's disease brain. Neurology 44:1090-6
Burkhardt, C; Kelly, J P; Lim, Y H et al. (1993) Neuroleptic medications inhibit complex I of the electron transport chain. Ann Neurol 33:512-7
Bennett, M C; Diamond, D M; Stryker, S L et al. (1992) Cytochrome oxidase inhibition: a novel animal model of Alzheimer's disease. J Geriatr Psychiatry Neurol 5:93-101
Parker Jr, W D (1991) Preclinical detection of Parkinson's disease: biochemical approaches. Neurology 41:34-6;discussion 36-7
Parker Jr, W D (1991) Cytochrome oxidase deficiency in Alzheimer's disease. Ann N Y Acad Sci 640:59-64
Parker Jr, W D; Filley, C M; Parks, J K (1990) Cytochrome oxidase deficiency in Alzheimer's disease. Neurology 40:1302-3
Parker Jr, W D; Boyson, S J; Luder, A S et al. (1990) Evidence for a defect in NADH: ubiquinone oxidoreductase (complex I) in Huntington's disease. Neurology 40:1231-4
Parker Jr, W D; Boyson, S J; Parks, J K (1989) Abnormalities of the electron transport chain in idiopathic Parkinson's disease. Ann Neurol 26:719-23

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