Protein found that determines critical step in brain development

Cell biologists at Utrecht University have discovered a key protein that serves as the basic element for the intracellular structure of nerve cells. This protein determines the development of the axon, the slender extension that sends information from the nerve cell to other nerve cells. The intracellular organisation collapses if the protein is removed from a mature nerve cell. This could mean that this particular protein plays a role in the development of neural development disorders, such as autism, and degenerative brain diseases such as Alzheimer’s. The results of the research will be published in the scientific journal Neuron on 16 December.

“With this discovery, we have answered a fundamental question about the unique development of nerve cells that has occupied neurologists and biologists for some time”, according to research head Casper Hoogenraad, Professor of Cell Biology at Utrecht University. Nerve cells develop from round stem cells that have a number of tiny protrusions. The cell biologists from Utrecht have discovered that the axon (the ‘transmitter’) always grows out of the protrusion that has the TRIM46 protein. After that, all of the other protrusions grow to become dendrites (the ‘receivers’). This means that TRIM46 determines the position of the axon, and with it the nerve cell’s asymmetrical structure, known as ‘polarity’.

Many diseases start in the cytoskeleton

TRIM46 appears to bind to the nerve cell’s cytoskeleton, a complex network of protein tubules that gives the cell its shape and controls the transport throughout the cell. In this way, TRIM46 acts as a critical scaffolding for the rapid construction and growth of the axon. Hoogenraad: “Several studies have shown that many diseases start when something goes wrong in the cytoskeleton. So that may also be the case with neural development disorders and degenerative brain diseases.”

Development disorders and degenerative brain diseases

When the location of the axon is determined, the orientation of the nerve cell’s cytoskeleton is fixed. But in development disorders and degenerative brain diseases, something goes wrong in this intracellular organisation, which makes it unclear as to what the nerve cell’s input and output is. Cellular proteins that belong in the axon end up in the dendrites, which can eventually cause the axon to atrophy.

Million-dollar question

“Our research has shown that exactly this process occurs as soon as we remove TRIM64 from the axon. But we have not yet proven that there is a relationship with any disease”, says Hoogenraad. “The million-dollar question now is: does TRIM46 also disappear in children with autism or in Alzheimer’s patients? If so, then we may have a new starting point for the development of therapies.”

This research was funded in part by an ERC Consolidator Grant awarded to Casper Hoogenraad.

Life Sciences

This research is an example of Science for Life, part of Utrecht University’s strategic research theme Life Sciences.

Publication

TRIM46 controls neuronal polarity and axon specification by driving the formation of parallel microtubule arrays

Sam F.B. van Beuningen, Lena Will, Martin Harterink, Anaël Chazeau, Eljo Y. van Battum, Cátia P. Frias, Mariella A.M. Franker, Eugene A. Katrukha, Riccardo Stucchi, Karin Vocking, Ana T. Antunes, Lotte Slenders, Sofia Doulkeridou, Peter Sillevis Smitt, A.F. Maarten Altelaar, Jan A. Post, Anna Akhmanova, R. Jeroen Pasterkamp, Lukas C. Kapitein, Esther de Graaff, Casper C. Hoogenraad (All authors are affiliated with Utrecht University)

Neuron, 16 december 2015: http://dx.doi.org/10.1016/j.neuron.2015.11.012.

Animation video about the transport in a nerve cell
A day in the life of a motor protein

More information

• News report (Dutch) and interview on the ERC Consolidator Grant for Casper Hoogenraad
• News report on the IBRO/Kemali International Prize for Research in the Field of Basic and Clinical Neuroscience 2016 for Casper Hoogenraad

Contact

Monica van der Garde, Press Spokesperson, Faculty of Science, m.vandergarde@uu.nl, +31 (0)6 13 66 14 38.