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Posted:
October 28, 2014
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Neurons
In a ground breaking paper just published in the international journal Neuron, an international consortium involving scientists and clinicians from Trinity College Dublin, led by their long term collaborator Dr John Landers of the University of Massachusetts has reported a new Motor Neuron Disease -associated gene (TUBA4A). The team have shown that they can identify new and important causes of Motor Neuron Disease (MND) through the detailed analysis of rare coding variations in DNA from people with MND.

Genes are a code within DNA used to make all the proteins in a human’s body. Some diseases are caused by faulty coding within our genes, leading to the manufacture of defective proteins. Finding these coding faults can help scientists to understand diseases like MND. The disease, which causes a gradual degradation and death of motor neurons, affects about 300 people in Ireland, with some 110 new cases reported each year.

Dr Landers’ group examined the DNA from 363 people with MND, each of whom also had another family member with the condition. They performed an analysis of every gene in the genome of these patients which generated trillions of individual DNA base cells. Piecing these together, they searched for patterns of rare damaging mutations that appeared more frequently in patients with MND than in people without the disease.

They found that more people than expected with MND had an unusual change in the code for a protein in nerve cells that transport vital building blocks from one part of the nerve cell to another. Damage to this transport system leads to dysfunction of the nerve, and understanding this may help scientists to find new treatments for MND.

This important discovery from Dr Lander’s laboratory, which required advanced DNA analysis by Irish scientist Dr Kevin Kenna, and used samples from the MND Research Group in Trinity College and other centres, has added another piece to the jigsaw of the understanding of the causes of MND.

Speaking about this discovery, Orla Hardiman, Professor of Neurology in Trinity College Dublin, Consultant Neurologist at Beaumont Hospital and one of the paper’s authors said: “We are very excited by Dr Landers’ finding for mutations in the gene TUBA4A in some forms of MND. We are particularly proud of the contribution of Dr Kenna, a young post-doctoral scientist who has recently completed his PhD in MND Genetics with our group in Trinity College Dublin.  This form of international collaboration across leading centres will help us to bring new treatments closer to the clinic.”

“We will continue to collect and analyse DNA from Irish patients with Motor Neuron Disease in collaboration with our colleagues in genetics, Dr Russell McLaughlin and Professor Dan Bradley at Trinity, as there are many discoveries still to be made in collaboration with our international colleagues,” she added.

A video describing this discovery and featuring Dr Kevin Kenna is available here: http://youtu.be/d1rCjNSNiI0

The paper is available from Neuron: http://www.cell.com/neuron/home

Media Contact

Yolanda Kennedy, Press Officer for the Faculty of Health Sciences |yokenned@tcd.ie | 01 896 3551

Posted:
February 27, 2014
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Neurons

Geneticists from Trinity College Dublin interested in ‘reverse engineering’ the nervous system have made an important discovery with wider implications for repairing missing or broken links. They found that the same molecular switches that induce originally non-descript cells to specialise into the billions of unique nerve cell types are also responsible for making these nerve cells respond differently to the environment.

The geneticists are beginning to understand how these molecular switches, called ‘transcription factors’, turn on specific cellular labels to form complex bundles of nerves. These bundles function to ensure we respond and react appropriately to the incredible amount of information our brains encounter. Understanding how to precisely program nerve cells could help to target missing or broken links following serious injury or the onset of degenerative diseases such as Alzheimer’s or Parkinson’s. 

Commenting on the importance and wider implications of this discovery, Assistant Professor in Genetics at Trinity, Juan Pablo Labrador said: “We know very little of how individual nerve cells are programmed to assemble into specific nerves in living organisms to make specific circuits, so our work is like reverse engineering the nervous system.”

“To restore damaged or missing connections in the nervous system – for example, after spinal cord injuries or degenerative diseases such as Alzheimer’s or Parkinson’s – we need to know how nerve cells are programmed to make those connections in the first place. For that we require a complex ‘builder’s manual’ that tells us how to program the neurons to make the connections. What we are doing in my lab is trying to write this manual.”

The nervous system can be thought of as an incredibly complex network of wires, which are all arranged into different, related bundles to coordinate complex tasks. The wires are the cellular extensions from the individual nerve cells that assemble into bundles to form specific nerves. The geneticists have begun to understand how varied combinations of transcription factors work to generate different nerve cells and direct their wiring to form specific nerves.

By studying the behaviour of individual nerve cells that make connections with muscles, the geneticists discovered specific ‘footprints’ of labels that induced these nerve cells to assemble into specific bundles that link to their target muscles. Individual transcription factors are only able to turn on specific labels to some extent. It is only the action of all of them together that programmes the nerve cells to turn on all the labels required.

The research was just published in the high-profile journal Neuron. The team led by Assistant Professor Juan Pablo Labrador, found that the actions of the transcription factor influencing nerve cell differentiation in flies (‘Eve’) controls nerve cell surface labels.

The team also showed that if these labels, targeted by Eve, are expressed erroneously, the nerve cells will not form the correct nerves. Additionally, the team discovered that different combinations of transcription factors including Eve work as codes for different groups of labels that guide individual nerve development.

A link to the journal article is available here.