Inborn errors of neurotransmitters and pterins
Neurotransmitters are a group of chemical messengers that enable the communication between the neurons in the syntactical cleft. For biosynthesis of the biogenic amines dopamine and serotonin, tetrahydrobiopterin (BH4) is an essential cofactor. Folates are chemically similar to BH4 and play a key role in different processes of the central nervous system.
Translation research projects
The role of BH4 in brain development
Our study aims to unravel the role of BH metabolism in brain development. We therefore model this pathway including de novo synthesis and recycling steps in the zebrafish embryos, but using both in situ hybridization and morpholino knockdowns as well as CRISPR knock out to analyze the neurological phenotype of the developing embryo.
Patient-specific induced pluripotent stem cells (iPSCs) and dopaminergic neurons as model systems for the study of neurotransmitter and BH4 deficiencies
Inherited neurotransmitter and BH4 deficiencies belong to the family of rare metabolic diseases. As a matter of fact, all of these diseases are difficult to investigate as the number of affected individuals is limited and animal models often do not satisfactorily reflect the observed human phenotype. Moreover, therapeutic intervention is complex and often can´t prevent disease progression. Therefore, better treatment options are urgently needed to improve the patient´s life.
Induced pluripotent stem cells (iPSCs) offer the unique possibility to study these rare inherited diseases using patient specific cells. By using reprogramming, we can generate iPSC lines from fibroblasts which have been donated by patients with a diagnosed and observed phenotype and a fully characterized genotype. As iPSCs can theoretically be differentiated into all specialized cell types of the human body, including neurons and hepatocytes, they provide us with a powerful tool to study disease processes in the dish and they can serve as a model system to identify the underlying molecular mechanisms leading to the observed phenotype. Moreover, differentiated diseased neurons can be used in a drug screening approach to find new drug targets and to develop new therapeutic regimen for the patients.
In collaboration with the DKFZ we have generated iPSC lines from patients with different defects in neurotransmitter and BH4 metabolism, including tyrosine hydroxylase and sepiapterin reductase. Currently, we are characterizing these iPSC lines focusing on relevant disease markers. Moreover, we are developing neuronal and hepatocyte differentiation protocols suitable for large-scale applications including drug screening / discovery but also for the investigation of the underlying molecular mechanisms leading to the frequently observed phenotypes in the patients.
Future perspectives and goals:
- Generation of iPSC-based patient-specific model cell lines reflecting known mutations in neurotransmitter and BH4 deficiencies
- Use of –omics approaches to identify aberrantly regulated cellular pathways causing the observed phenotypes
- Screening of small molecule libraries using iPSC- and neuron-based models to identify novel drug candidates and disease mechanisms
- Identification of new chaperones which are able to stabilize the defective enzymes of the BH4 and neurotransmitter synthesis pathways