Brain amino acid homeostasis requires the actions of transporters, enzymes and cofactors. Our project focuses on three subjects:
- L-serine metabolism and serine deficiency
- amino acids
- Vitamin B6 transport
L-serine and serine deficiency
L-serine, a non-essential amino acid, plays a central role in cellular proliferation and severe brain dysfunction may occur when L-serine, and as a consequence D-serine and glycine, are not available in adequate amounts. 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency is a disorder of L-serine biosynthesis. Affected children show:
- congenital microcephaly
- severe psychomotor retardation
- intractable seizures.
In this project the relationship between the 3-PGDH deficiency and seizures is studied at the cellular level. We investigate the effects of L-serine deficiency on the function of the NMDA receptor complex, which plays a significant role in synapse refinement, neuronal plasticity and excitotoxicity.
D-amino acids
Experimental evidence strongly indicates that D-amino acids are present in the central nervous system and play a role in normal development and probably in the pathogenesis of psychiatric disease as well. The neutral D-amino acid D-serine was shown to be synthesised within the mammalian brain and functions as a specific NMDA receptor ligand. Not only D-serine, but other neutral D-amino acids such as D-alanine and D-cysteine can activate NMDA receptors. In contrast, the origin and function of most
D-amino acids remains elusive. In this project, we therefore aim to answer:
- Which neutral D-amino acids are actually present in the CNS?
- How are these D-amino acids synthesised, transported and metabolised?
- What is their exact role in psychiatric disorders of cognition and behaviour?
Vitamin B6 transport
The active form of vitamin B6, pyridoxal phosphate, plays the role of cofactor in numerous metabolic conversions, among which neurotransmitter synthesis and amino acid metabolism. Pyridoxine dependent seizures clearly illustrate the important role for pyridoxal phosphate in the brain. The mechanism by which vitamin B6 enters the brain is currently entirely unknown. It is generally accepted that a transport system is present in choroid plexus but not a single pyridoxine transporter has been characterized at the molecular level to date. Our project aims at the molecular elucidation and biochemical characterisation of the vitamin B6 transporter in the choroid plexus.
Group
The following people participate in this project:
Tom de Koning (project leader)
Leo Klomp (project leader)
Nanda Verhoeven-Duif (project leader)
Wouter Visser (post-doc)
Leyla Tabatabaie (PhD student)
Sabine Fuchs (AGIKO)
Monique Albersen (PhD student)
Floris Hofstede (fellow)
Marjolein Bosma (technician)