Discoveries Could Lead to New Strategies for ALS
January 19, 2005
[QUICK SUMMARY: Key genes governing the ability of developing brain cells to connect properly to the spinal cord could produce new insights for repair of damage in ALS.]
In the journal Neuron, researchers report on key genes that appear to be crucially active in developing motor neurons, the cells of the brain that connect to the spinal cord and ultimately control muscles, which die during disease progression in ALS.
Funded in part by The ALS Association (ALSA), Jeffrey Macklis, M.D., D.HST, director of the Massachusetts General Hospital-Harvard Medical School Center for Nervous System Repair, Boston, Mass., and colleagues identified approximately three dozen genes crucial for the development of these neurons. They found a series of genes that control different aspects of the development of these motor neurons that reach from the brain down into the spinal cord.
These genes also provide the first markers that highlight the specific neurons that die in ALS within the brain’s cortex. Two types of neurons those in the brain’s cortex and spinal motor neurons in the spinal cord are linked and are affected by the disease process in ALS.
In this first of several papers on the topic, the investigators explored the function of one gene that appears to be critical to the proper linkage of the cortex to the spinal cord. Mice engineered to lack that gene fail to form any connections from the cortical motor neurons to the spinal motor neurons.
A critical aspect of motor neurons is their “ability to extend an extremely long axon to precise locations within the spinal cord. Here,” the researchers write in their report in the January 20 issue of the journal, “we identify several molecules specifically expressed in (these neurons) that might play important roles in (their) axonal growth and guidance.”
Commenting on the implications of the findings, Macklis said, “Some of these genes and molecules might be manipulated to enhance the survival or function of diseased corticospinal motor neurons, and we hope that these signals might be used to control stem cells to replace diseased corticospinal motor neurons.”
Progress from a number of labs shows “how the motor neurons in the spinal cord itself develop and, more recently, how they might be replaced,” Macklis noted. “Our work aims at a similar understanding and therapeutic goal with the ‘upper half’ of ALS the important corticospinal motor neurons.”
One of the most complex structures in living creatures is the human cerebral cortex, the part of the brain governing thought, memories, and voluntary movement. When the cortex is forming, what tells the myriad of developing nerve cell where to go and what to do? The answer may enable scientists to devise repairs for damaged nervous systems in diseases such as ALS and in spinal cord injury.
Strategies for treating these conditions have been limited by a lack of understanding of the molecular controls over the developing brain. “The incredible complexity of the brain and its cerebral cortex has made it very difficult to study these neurons until now,” Macklis continued. “We hope that our new approaches, first described in this paper, will allow the field to make rapid progress.”
The investigators produced 99% pure collections of different neurons from mouse embryos and newborn mice with a cell sorting machine. They could then look at each type alone to find what genes are read out at different times during development.
Microarray technology allows scientists to see which genes are transcribed at any given time, using DNA mounted on silicon chips. Samples of the cells are read by the microarray, which finds matches to active gene sequences.
With this publication, the researchers show that specific types of cortical neurons can now be purified from the complex cortex at distinct and critical stages of development. Undoubtedly, their approach will help decipher the genetic babble of the human brain and could produce new strategies for treating ALS.
Read more about corticospinal motor neuron development.
