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 (1) how is the expression of alpha-synuclein controlled, since over- expression might predispose to protein aggregation; (2) what is the chemical nature of these aggregates, and do they contain some form of damaged alpha-synuclein. These two complementary approaches allow us to ask if there are genetic determinants that increase alpha-synuclein expression and to make inferences as to the kinds of damage, and what factors in the cell or environment might contribute to the damage.We have found that different alleles in a polymorphic short tandem repeat in the promoter of alpha-synuclein has a three-fold effect on gne expression; this same repeat has been implicated in PD in some association studies. We are also examining two large families with apparent autosomal dominant PD and carrying out linkage analysis in order to find other genes which, when mutated, can cause a highly penetrant form of inherited PD.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Intramural Research (Z01)
Project #
1Z01HG000117-06
Application #
6681507
Study Section
(GDRB)
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2002
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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Ulmer, Tobias S; Bax, Ad; Cole, Nelson B et al. (2005) Structure and dynamics of micelle-bound human alpha-synuclein. J Biol Chem 280:9595-603
Simon-Sanchez, Javier; Hanson, Melissa; Singleton, Amanda et al. (2005) Analysis of SCA-2 and SCA-3 repeats in Parkinsonism: evidence of SCA-2 expansion in a family with autosomal dominant Parkinson's disease. Neurosci Lett 382:191-4

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