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Jost Leemhuis – Reelin signalling and psychiatric diseases

The brain has a surprisingly well-ordered architecture. The layered structure of the mature cerebral cortex is formed during development. The neurons of these horizontal layers are important for the interplay of electrochemical impulses that enable us to think, feel and remember. This layered structure depends on a molecule known as Reelin and other proteins that regulate the migration of neurons and their positioning in the developing brain. Dr. Jost Leemhuis from the Centre for Neuroscience (ZfN) at the University of Freiburg is investigating the molecular processes at and below cell membranes that are triggered by the signalling molecule Reelin. The pharmacologist is convinced that “we need to abandon the idea of linear signalling”. Leemhuis’ results from this and other projects he intends to do in the future are also related to neurodegenerative diseases such as Alzheimer’s and psychiatric conditions such as depression and schizophrenia.

Dr. med. Jost Leemhuis © Dr. med. Jost Leemhuis

It is known from experiments with knock-out mice carried out a few years ago that the glycoprotein Reelin is an important signalling molecule; it helps regulate processes leading to the correct positioning of neurons in the developing brain. Further investigations with mice have given insights into the function of Reelin on the cellular level: for example, the molecule stimulates the development of dendrites and axon endings. Inside neurons, Reelin regulates the transport of cargo via vesicles that take newly synthesised proteins to their final cellular destination, thereby enabling neurons to function properly. The growth and the mobility of cellular projections along with the vesicular transport are closely linked with the dynamic processes occurring in the cellular actin skeleton. The scaffold of interconnected actin molecules that undergoes constant generation and degradation provides the cell with a flexible outer form and an internal network for the transport of cargo. “For us it seemed logical that the signalling processes involving the Reelin molecule and the actin skeleton must be inter-related,” said Dr. Jost Leemhuis, head of a group of researchers at the Centre for Neuroscience (ZfN) in Freiburg.

Molecular switches for the transfer of external signals

Brain slices of a normal mouse (top left and bottom left) and of a reeler mouse (top right and bottom right). The brain of reeler mice lacks the Reelin protein and therefore does not develop the layered structure of a normal mouse brain. © Christian Cremer

A few years ago, Leemhuis (b. Düsseldorf, 1969) and his colleagues showed that this was actually the case. Working at the Centre for Neuroscience (ZfN) founded by Prof. Dr. Michael Frotscher, they were able to combine their expertise with the know-how of the group of researchers led by the Freiburg neuroscientist Dr. Hans H. Bock. Bock owned different mouse models that the researchers used to investigate the function of Reelin. As a result of their work, they were able to show that a link existed between Reelin signalling and the actin skeleton.

Leemhuis’ background is in pharmacology and cell biology. He studied medicine at the University of Düsseldorf between 1990 and 1997, earned his doctoral degree in biochemistry in 1998 and spent his postdoctoral study period with the Freiburg pharmacologist Prof. Dr. Klaus Aktories, amongst others. After several research stays abroad, he habilitated on Rho GTPases at the Institute of Pharmacology in 2007. The small Rho GTPase molecules are important “molecular switches” that react to numerous external cues, including cues from the extracellular matrix protein Reelin. Reelin usually docks to two extracellular receptors - the apolipoprotein E receptor-2 (ApoER2) and the very low-density lipoprotein receptor (VLDLR). These receptors are also involved in the cellular lipid metabolism and have been found to play a role in the development of Alzheimer’s disease. The Reelin receptor translates the signal about its conformational change into the cell, where it triggers a Rho GTPase protein.

The findings obtained in cooperation with the group of researchers led by Dr. Hans H. Bock revealed that the Reelin-mediated signalling pathway mainly involved the two Rho GTPases Cdc42 and Rac1. These two molecules regulate the development and motility of cellular projections; Cdc42 is also involved in vesicular transport. The researchers also found that both molecules exert their effect by switching on or off the regulators of the actin skeleton. The finding therefore led to the identification of the molecular interface between the cellular and molecular level.

One disease, many signals

Reelin docks to either one of its two extracellular receptors; a signalling cascade then activates intracellular Cdc42 and Rac1, which leads to the well-known Reelin effects. Reelin signalling is also linked to other signalling pathways (e.g., the glutamate-NMDA signalling pathway shown in this diagram). © Dr. med. Jost Leemhuis

Rho GTPases such as Cdc42 or Rac1 also play key roles in many other processes during mammalian development, including processes such as cell division or synaptic plasticity. Over the last few years, Leemhuis and other researchers around the world have provided increasing evidence that Rho GTPases control many aspects of cell behaviour through the regulation of multiple signalling pathways. Rho GTPases can be activated by Reelin receptors as well as by many other receptors, including the NMDA receptor. How does a Rho GTPase “know” which type of receptor, and hence which signal, led to its activation. How does the molecule know which type of cellular response to induce – vesicular transport, axonal cone growth or cell division? “So-called guanine nucleotide exchange factors (GEFs) play a major role in the decision taken by the Rho GTPases,” said Leemhuis. GEFs activate Rho GTPases and enable them to exert their effect on different cellular targets. It is believed that each GEF type induces a specific signalling pathway. “We are currently working towards a more detailed understanding of these processes,” said Leemhuis.

It is quite clear that the Reelin-mediated signalling processes are a lot more complex and branched then previously assumed. “These complex signalling processes are also associated with the development of Alzheimer’s or psychiatric conditions such as depression, schizophrenia and bipolar disorder,” said Leemhuis going on to add that “a broad systems biology approach is needed to be able to identify the causes of these diseases.” Working with systems biologists and physicists led by Prof. Jens Timmer and psychiatry experts led by Dr. Claus Normann from Freiburg, Leemhuis and his colleagues have launched the interdisciplinary ReelinSys (systems biology of Reelin-associated neuropsychiatric disorders) project whose goal is to bring together interdisciplinary researchers. “Diseases such as Alzheimer’s and schizophrenia are not the result of a single mutated gene,” said Leemhuis. “These diseases are always the result of many causes. If we are able to shed light on the complex signalling network that leads to the development of such diseases, then we will at some stage be able to develop a therapy that targets many different disease-causing aspects, which is what is already happening in cancer treatment.” Leemhuis is convinced that the idea of linear signalling pathways needs to be abandoned along with the idea that a single researcher is able to make a groundbreaking discovery without working in cooperation with others.

Further information:

PD Dr. med. Jost Leemhuis
Institute of Experimental and Clinical Pharmacology and Toxicology
Centre for Neuroscience
Albertstrasse 23
79104 Freiburg im Breisgau
Tel.: 0049 (0)761 203 5330
E-mail: jost.leemhuis(at)pharmakol.uni-freiburg.de

Website address: https://www.gesundheitsindustrie-bw.de/en/article/news/jost-leemhuis-reelin-signalling-and-psychiatric-diseases