Biomarker Parkinson's disease
Prof. Dr. Ullrich Wüllner
Cooperation Unit Leader
Sigmund-Freud-Str. 25
53105 Bonn

ullrich.wuellner@dzne.de
 +49 228 287-15712

Areas of investigation/research focus

Background and Significance
Rapid advancement has been made in the field of epigenetics (1). In addition to genetic and proteomic studies, assessment of global DNA methylation and the histone state are emerging as crucial components of understanding neuro-psychiatric diseases (2). Beyond the actual code of a regulatory DNA sequence, several additional levels of epigenetic transcriptional control have become apparent recently. Methylation of CpG-dinucleotides (cytosines) in the DNA constitutes the basic mechanism of gene expression regulation and a frequent biochemical modification of DNA in the human genome. Hypermethylation of CpG rich regions (“islands”, CGI) is often found in regulatory 5’-regions and methylation-dependent silencing of tumor suppressor genes is a widely acknowledged mechanism in the pathogenesis of cancer.

While believed to represent a fixed state at least in the adult, a role for dynamic methylation is emerging in neural gene expression regulation (1,3). In addition to classic monogenetic epigenetic disease, i.e. Beckwith-Wiedeman and Prader-Willi syndrome, recent data point to an epigenetic component also of other neuro-psychiatric disorders (4). 

 more Infos

Research topic
Epigenetic processes could also be important in aging processes as many genes undergo profound changes in methylation in mid-life (3). 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 (5). 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 (5-7).

Challenges
In addition to 5-Methylation of DNA, acetylation, methylation, phosphorylation and ubiquitination of histones probably contributes to the graded genetic risk in neuro-psychiatric disorders. As of yet, only few studies have investigated the complex modification of histones and the identification of the multi-protein complexes and co-factors (SMRT, NCor, Sin5a, etc.) required for HDACs is just beginning (7,8).

Current Activities
Ongoing studies address the question whether changes in the methylation pattern are present in peripheral blood monozytes of PD patients, too and might serve as a biomarker. Further the role of the methyl-binding protein MeCP2 on alpha-synuclein expression is characterized. The effect of dopaminergic stimulation on methylation is another current project.

Research aims and  perspectives
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. 

Literature cited

  1. Suzuki MM, Bird A. Nat Rev Genet 2008; 9: 465–76.
  2. Huang HS, Akbarian S. PLoS One. 2007, 29. Aug.; 2(8): e809.
  3. Siegmund KD, Connor CM, Campan M et al. PLoS ONE 2007; 2: e895.
  4. Chahrour M, Zoghbi HY. Neuron 2007; 56: 422–37.
  5. Jowaed A, Schmitt I, Kaut O, Wüllner U. JNeurosci, 2010 30(18): 6355–92010.
  6. Kaut O, Schmitt I, Wüllner U. Neurogenetics. 2012 (1): 87–91. Epub 2012, 12. Jan.
  7. Weng MK, Zimmer B, Pöltl D, Broeg MP, Ivanova V, Gaspar JA, Sachinidis A, Wüllner U, Waldmann T, Leist M. PLoS One. 2012; 7(5): e36708. Epub 2012, 9. Mai.
  8. Schmitt I, Wüllner U, van Rooyen JP, Khazneh H, Becker J, Volk A, Kubisch C, Becker T, Kostic VS, Klein C, Ramirez A. Eur J Hum Genet. 2012 23. Mai. doi: 10.1038/ejhg.2012.84. [elektronische Vorabveröffentlichung]

Previous work
In the past, the Neurobiology research lab of Prof. Wüllner, who served as the head of the gene bank in the Parkinson Competence Network, investigated genetic variants of coding DNA sequences in Parkinson’s disease (PD) [Paus, 2004, Möller 2004, Healy, 2004; Buervenich, 2005, Mueller, 2005; Biskup, 2005, Wüllner, 2005; Fuchs, 2008]. Transcriptional regulation has been a major focus along the research on polyglutamine diseases: the lab identified the transcriptional repressor activity of ataxin3, the disease protein in spinocerebellar ataxia type3, a polyglutamine disease characterized by intraneuronal protein aggregates, which is mediated by histone deacetylase HDAC3 (Evert, 1999. 2001, 2003, 2006a, b; Müller 2009). Further, the epigenetic regulation of expression of the inflammatory mediator tumor necrosis factor (TNF)-alpha was characterized the and found that the methylation state of solitary CpGs in the TNF-alpha promoter determined TNF expression in specific cell populations (Pieper, 2008). The methylation pattern of the TNF-alpha promoter was altered in patients with Alzheimer’s disease, too (Kaut, submitted). Comparing DNA from different brain regions of PD patients and neurologically healthy, age and sex matched controls by bisulfite sequencing it was found that a concealed promoter in the SNCA gene is hypomethylated in PD (Jowead, 2010).

Impact and perspective
The importance of epigenetics in diseases of the nervous system is just beginning to emerge. Epigenetic changes likely confer the missing link between genes and environment and probably contribute to a graded (epi) genetic risk for neurodegenerative disease. By and large, very little is known about methylation of specific genes and putative modifications of histones in neurodegenerative diseases. If disease specific changes were identified, the implications are enormous. Alterations of the methylation state might allow early diagnosis using methyl specific PCR and other techniques. As tools are being devolped to modulate the methylation state, sequence-specific modulation of methylation may eventually open novel therapeutic approaches.

Schlüsselpublikationen

Bedarf, Hildebrand, Coelho, Sunagawa, Bahram, Goeser, Bork, Wüllner. Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naïve Parkinson's disease patients. Genome Medicine. 2017 Apr 27; 9 doi: 10.1186/s13073-017-0428-y
Ina Schmitt, Oliver Kaut, Hassan Khazneh, Laura deBoni, Ashar Ahmad, Daniela Berg, Christine Klein, Holger Fröhlich, Ullrich Wüllner. L-dopa increases α-synuclein DNA methylation in Parkinson's disease patients in vivo and in vitro. Movement Disorders. 2015 Oct 31; 30:1794-1801. doi: 10.1002/mds.26319
Jun Mitsui, Takashi Matsukawa, Hiroyuki Ishiura, Yoko Fukuda, Yaeko Ichikawa, Hidetoshi Date, Budrul Ahsan, Yasuo Nakahara, Yoshio Momose, Yuji Takahashi, Atsushi Iwata, Jun Goto, Yorihiro Yamamoto, Makiko Komata, Katsuhiko Shirahige, Kenju Hara, Akiyoshi Kakita, Mitsunori Yamada, Hitoshi Takahashi, Osamu Onodera, Masatoyo Nishizawa, Hiroshi Takashima, Ryozo Kuwano, Hirohisa Watanabe, Mizuki Ito, Gen Sobue, Hiroyuki Soma, Ichiro Yabe, Hidenao Sasaki, Masashi Aoki, Kinya Ishikawa, Hidehiro Mizusawa, Kazuaki Kanai, Takamichi Hattori, Satoshi Kuwabara, Kimihito Arai, Shigeru Koyano, Yoshiyuki Kuroiwa, Kazuko Hasegawa, Tatsuhiko Yuasa, Kenichi Yasui, Kenji Nakashima, Hijiri Ito, Yuishin Izumi, Ryuji Kaji, Takeo Kato, Susumu Kusunoki, Yasushi Osaki, Masahiro Horiuchi, Tomoyoshi Kondo, Shigeo Murayama, Nobutaka Hattori, Mitsutoshi Yamamoto, Miho Murata, Wataru Satake, Tatsushi Toda, Alexandra Dürr, Alexis Brice, Alessandro Filla, Thomas Klockgether, Ullrich Wallner, Garth Nicholson, Sid Gilman, Clifford W. Shults, Caroline M. Tanner, Walter A. Kukull, Virginia M.-Y. Lee, Eliezer Masliah, Phillip A. Low, Paola Sandroni, John Q. Trojanowski, Laurie Ozelius, Tatiana Foroud, Shoji Tsuji. Mutations in COQ2 in familial and sporadic multiple-system atrophy the multiple-system atrophy research collaboration. New England Journal of Medicine. 2012 Dec 31; 369:233-244. doi: 10.1056/NEJMoa1212115
Philipp Koch, Peter Breuer, Michael Peitz, Johannes Jungverdorben, Jaideep Kesavan, Daniel Poppe, Jonas Doerr, Julia Ladewig, Jerome Mertens, Thomas Tüting, Per Hoffmann, Thomas Klockgether, Bernd O. Evert, Ullrich Wüllner, Oliver Brüstle. Excitation-induced ataxin-3 aggregation in neurons from patients with Machado-Joseph disease. Nature. 2011 Dec 21; 480:543-546. doi: 10.1038/nature10671
Jowaed A, Schmitt I, Kaut O, Wüllner U. Methylation regulates alpha-synuclein expression and is decreased in Parkinson's disease patients' brains. J Neurosci. 2010 Jan 01; 30:6355-9. doi: 0.1523/JNEUROSCI.6119-09.2010

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