of the Max - MDC

RNA Editing and
Hyperexcitability Disorders
Jochen C. Meier
(Helmholtz Fellow)
I
n a healthy organism, a balance is maintained between the excitation and inhibition of electrical
impulses generated by neurons in the brain. Deregulation of this balance results in nervous system
disorders. A core aspect of our work concerns the study of the brain at the molecular level, by investigating
a post-transcriptional enzymatic process known in research as “RNA editing”. Thereby, after
the DNA text of the genes has been transcribed into RNA, individual letters are replaced with others
by enzymatic processing. As a result, the original genetic text no longer corresponds exactly to the
resulting protein text. By this means, the cell succeeds in disregarding the information coded in the
genome, and through specific alterations can give its own genetic text a completely different meaning.
RNA editing is evolutionarily very old. Nevertheless, in humans only a few editing sites were
identified so far. We search for such sites in the nervous system in order to find out what role they
play in nervous system disorders, such as temporal lobe epilepsy. Within this context, we are more
closely scrutinizing the glycine receptor – one of the neuronal receptors that inhibit electrical impulses
in the brain.
Synaptic and tonic inhibition – Glycine receptor
dynamics from the point of view of gephyrin
Neurotransmitter receptors are highly mobile entities within
the neuronal plasma membrane. Enrichment of postsynaptic
domains with neurotransmitter receptors therefore reflects
a dynamic equilibrium between less mobile, synaptic and
highly mobile, non-synaptic receptors. The diffusion rate is
slowed down by reversible glycine receptor binding to the
postsynaptic scaffolding protein gephyrin. These receptors
contribute to synaptic inhibition of action potential generation
whereas highly mobile receptors, which escaped postsynaptic
anchoring, are involved in tonic inhibition of neuron
firing. In the past, we could identify several novel splice
variants of gephyrin, which were uncovered to adopt specific
functions in the hippocampus. There, certain gephyrin
splice variants (C5-gephyrins) were found to ensure exclusion
of glycine receptors from anchoring at GABAergic postsynaptic
domains, which constitutes the molecular basis for
hippocampal glycinergic tonic inhibition and provides us
with the possibility to develop novel pharmaceutical concepts
for treatment of nervous system disorders.
Deciphering the molecular basis of Molybdenum
cofactor biosynthesis
Gephyrin has enzymatic activity. It is a multidomain protein
that emerged from fusion of two bacterial proteins, MogA
and MoeA. These Escherichia Coli proteins contribute to the
biosynthesis of molybdenum cofactor (Moco), which is an
essential component of cellular redox reactions. Mammalian
gephyrins are still able to synthesize Moco because the
enzymatic activity of the E. Coli homologous domains is
preserved. In mammals, the most important Molybdenum
enzyme is sulfite oxidase, which catalyzes the last step in
the degradation of sulfur-containing amino acids and sulfatides.
Human Moco deficiency is a hereditary metabolic
disorder characterized by severe neurodegeneration resulting
in early childhood death. We have found that C5-
gephyrins are no longer enzymatically active, and because
these particular gephyrins are expressed in liver, where
Moco is synthesized, they are expected to contribute to regulation
of Moco synthesis. Therefore, one aspect of our work
concerns the molecular and functional dissection of alternatively
spliced gephyrins, using truncated and mutant
expression constructs in a variety of cell types.
RNA editing emerges as a compensatory albeit
pathophysiological mechanism in hyperexcitability
disorders
Tonic inhibition of neuron firing plays a pivotal role in brain
information transfer because it provides a global control of
neuronal excitability. A large body of evidence has implicated
impaired hippocampal GABAergic inhibition in enhanced
susceptibility of neurons to become hyperexcitable and to
generate epileptiform discharges. The GABA(A) receptor
homologous glycine receptor has more recently been
involved in hippocampal tonic inhibition. Previously, we
Function and Dysfunction of the Nervous System 181