- Molecular pathogenesis of Parkinson´s disease, Multiple system atrophy , SCA

in Bonn

Epigenetic processes could also be important in aging processes as many genes undergo profound changes in methylation in mid-life. It is tempting to speculate that age-related diseases (e.g. Alzheimer's, Parkinson's disease; AD, PD) are tailored by alterations of the methylation pattern.
Indeed, PD is only rarely inherited following Mendelian laws, futhermore twin studies suggest that genetic factors contribute only to a minor extent to sporadic PD. Classic genetic factors are stronger only in patients with an very early disease onset. On the one hand, it is assumed that the combination of various genetic polymorphisms each of which alone is not pathogenic increases the likelihood to develop PD. On the other hand, we put forward the hypothesis that alpha-synuclein (SNCA) methylation confers a susceptibility for PD. SNCA is a major risk gene for PD and increased SNCA gene dosage results in a parkinsonian syndrome in affected families.
We found that methylation of human SNCA intron1 decreases gene expression while inhibition of DNA methylation activated SNCA protein expression. Methylation of SNCA intron1 was reduced in DNA from sporadic PD patients’ substantia nigra, putamen and cortex, pointing towards a yet unappreciated epigenetic regulation of SNCA expression in PD. Aberrant DNA methylation might thus constitute a pathogenic mechanism for PD and possibly also other neurodegenerative diseases.
To understand the complex genetic aetiology studies of large numbers of patients, family members and healthy control persons are required. To facilitate such studies the German PD Gene Bank (Genbank Parkinson´sche Krankheit Deutschland, GEPARD) was established in Bonn as part of the BMBF-sponsored PD competence net (Kompetenznetz Parkinson, KNP). GEPARD collects and stores DNA samples of PD patients, their relatives and controls. Currently, GEPARD contains approximately 3000 DNA samples.
The epigentics group will focus on the interweaved pattern of DNA methylation on the one hand and histone acetylation and – methylation on the other hand of key genes in PD to provide an integrated chromatin analysis of DNA methylation patterns and histone modifications. Specifically, the methylation state of SNCA will be determined in various PD tissues (CNS and peripheral lymphocytes) and the global methylation status will be assessed in a genome wide approach to identify other differentially methylated genes. Established techniques will be developed further in collaboration with the NGFNplus epigenetics platform (longterm goal: methylation chips for PD) with a particular focus on expression-relevant sequence regions.
http://www.neurologie.uni-bonn.de/wuellner.htm

Technologies

We analyze the molecular steps leading to neurodegeneration and the physiological protein functions. We have developed transgenic models, employ a wide array of techniques in molecular biology and epigenetics

Publications

RECENT PUBLICATONS


1: Schmitt I, Wüllner U, van Rooyen JP, Khazneh H, Becker J, Volk A, Kubisch C,
Becker T, Kostic VS, Klein C, Ramirez A. Variants in the 3'UTR of SNCA do not
affect miRNA-433 binding and alpha-synuclein expression. Eur J Hum Genet. 2012
May 23. doi: 10.1038/ejhg.2012.84. [Epub ahead of print] PubMed PMID: 22617348.


2: Weng MK, Zimmer B, Pöltl D, Broeg MP, Ivanova V, Gaspar JA, Sachinidis A,

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Contact

Prof. Dr. Ullrich Wüllner, Stellv. Direktor
Klinik und Poliklinik für Neurologie
Universitätsklinikum Bonn
Sigmund-Freud-Straße 25
53105 Bonn

Phone: x49 (0) 228 2871 5712 / 5697
Fax: x49 (0) 228 2871 5024

Email: