In 1997, my coworkers and I discovered that missense mutations in the gene encoding the presynaptic protein, alpha-synuclein, could cause a rare autosomal dominant, early onset form of Parkinson's disease (PD). Aggregates of this same protein are found in Lewy bodies and neurites, the characteristic lesions seen in the brains of all PD patients, the vast majority of whom do NOT have mutations in the alpha-synuclein gene. We are investigating why aggregates of this protein develop in PD patients by asking how is the expression of alpha-synuclein controlled, since over- expression due to triplication of the gene causes protein aggregation and disease. We have found that different alleles in a polymorphic short tandem repeat in the promoter of alpha-synuclein has a three-fold effect on gene expression; this same repeat has been implicated in PD in some association studies. In the past year, we have also been investigating the role of alpha-synuclein in lipid metabolism and have found that mice deficient in this protein have abnormalities in mitochondrial cardiolipin levels and fatty acid composition. finally, we are also examining three large families with familial PD and carrying out linkage analysis in order to find other genes which, when mutated, can cause a highly penetrant form of inherited PD. In two families with apparent autosomal dominant PD, the cuasative mutation has been found and w are preparing to extend our studies to allow us to provide testing results to family members who wish to have it. In this way, we will begin to study presymptomatic individuals and attempt to follow the development of disease and intervene should a potential protective treatment become available. In the third family, with autosomal recessive PD, we have made progress in localizing the gene responsible to one small region of the human genome. This is the fist step twoards identifying the particular gene involved.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Intramural Research (Z01)
Project #
1Z01HG000117-09
Application #
7146858
Study Section
(GDRB)
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Human Genome Research
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Hoepken, Hans-Hermann; Gispert, Suzana; Morales, Blas et al. (2007) Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. Neurobiol Dis 25:401-11
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Chiba-Falek, Ornit; Kowalak, Jeffrey A; Smulson, Mark E et al. (2005) Regulation of alpha-synuclein expression by poly (ADP ribose) polymerase-1 (PARP-1) binding to the NACP-Rep1 polymorphic site upstream of the SNCA gene. Am J Hum Genet 76:478-92

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