Abstract
Parkinson's disease (PD) is a multifactorial disorder with complex etiology. The most prevalent PD associated mutation, LRRK2-G2019S is linked to familial and sporadic cases. Based on the multitude of genetic predispositions in PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patients' genetic background act as susceptibility factors for developing PD. To assess LRRK2-G2019S modifiers, we used human induced pluripotent stem cell-derived neuroepithelial stem cells (NESCs). Isogenic controls distinguish between LRRK2-G2019S dependent and independent cellular phenotypes. LRRK2-G2019S patient and healthy mutagenized lines showed altered NESC self-renewal and viability, as well as impaired serine metabolism. In patient cells, phenotypes were only partly LRRK2-G2019S dependent, suggesting a significant contribution of the genetic background. In this context we identified the gene serine racemase (SRR) as a novel patient-specific, developmental, genetic modifier contributing to the aberrant phenotypes. Its enzymatic product, D-serine, rescued altered cellular phenotypes. Susceptibility factors in the genetic background, such as SRR, could be new targets for early PD diagnosis and treatment.
| Original language | English |
|---|---|
| Journal | Parkinsonism and Related Disorders |
| Volume | 67 |
| Pages (from-to) | 48-55 |
| Number of pages | 8 |
| ISSN | 1353-8020 |
| DOIs | |
| Publication status | Published - 10.2019 |
Funding
The JCS lab is supported by the Fonds National de la Recherche (FNR) ( CORE , C13/BM/5791363 ). JW, DG, JJ, and XQ are supported by fellowships from the FNR ( AFR, Aides à la Formation-Recherche ) and SN had a doctoral school position from the Doctoral School in Systems and Molecular Biomedicine of University of Luxembourg . This is an EU Joint Programme – Neurodegenerative Disease Research (JPND) project ( INTER/JPND/14/02 ; INTER/JPND/15/11092422 ). Further support comes from the SysMedPD project which has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 668738 . We thank Xiangyi Dong for her assistance in the laboratory. CK is supported by the DFG through FOR2488 (P1) . We thank the Wellcome Trust Sanger institute , its funders, collaborators and Life Tech limited for supporting us with cell lines. We thank Prof. Dr. Thomas Gasser from the Universitätsklinikum Tübingen, Prof. Dr. Hans R. Schöler from the Max-Planck-Gesellschaft and Dr. Jared Sterneckert from the CRTD for providing us with cell lines. We thank the NINDS repository for providing cell lines. Microarrays were performed with EMBL GeneCore genomics core facility. We thank Aurélien Ginolhac for the preliminar microarray analysis. Bioinformatics analyses presented in this paper were carried out in part using the HPC facilities of the University of Luxembourg (see http://hpc.uni.lu ). Amino acid measurements were performed at the LACDR, Analytical Biosciences, Leiden University. EG acknowledges support by the Fonds Nationale de la Recherche (FNR) through the National Centre of Excellence in Research (NCER) on Parkinson's disease ( I1R-BIC-PFN-15NCER ) and as part of the project MitoPD, under the auspices of the bilateral e:Med program by the German Federal Ministry of Education and Research and the FNR ( INTER/BMBF/13/04 ).
Research Areas and Centers
- Research Area: Medical Genetics
