Authors (left to right): Francesco DiGiorgio, Monica Carrasco, Tom Maniatis, Michelle Siao, Kevin Eggan
Amyotrophic Lateral Sclerosis, also known as ALS or Lou Gehrig’s disease, is a devastating neurodegenerative condition caused by the death of motor neurons. The progressive loss of motor neurons in ALS patients results in total paralysis and muscle degeneration. ALS is a late onset disease with a median survival of 3 to 5 years after diagnosis. The molecular and cellular mechanisms that lead to motor neuron death in ALS are not well understood, and as a consequence there are no effective treatments. Even fundamental questions, such as whether motor neurons in ALS patients die because of intrinsic problems or are instead poisoned by other cells, remain to be answered. The slow progress in understanding ALS results in part from the cellular complexity of the spinal chord where the motor neurons reside, and the muscles to which they project.
We reasoned that a robust in vitro model system in which the affects of molecular and cellular players implicated in ALS pathology could be tested on motor neurons might lead to a better understanding of cellular interactions in the disease. In the May issue of Nature Neuroscience, our labs report the results of a collaborative effort to establish such an in vitro model system to study ALS.
This publication (authored by DiGiorgio, Carrasco, Siao, Maniatis and Eggan) describes the development of a system based on the in vitro differentiation of mouse embryonic stem (ES) cells bearing a human gene known to cause ALS. In vitro differentiation of these ES cells generated motor neurons and other cell types found in the spinal chord. Using these cultured cells, we found that motor neurons display abnormalities similar to those observed in both ALS patients and in transgenic animals carrying the human ALS gene. The most striking difference between normal and ALS motor neurons was survival in long term culture. To determine whether this poor survival is an intrinsic property of the ALS motor neurons we cultured them with glial cells derived from wild type mice or mice bearing the human ALS gene. Remarkably, we that found glia bearing the human ALS gene adversely affected the survival of both normal and ALS motor neurons. However, the affect on ALS motor neurons was significantly greater, revealing a negative synergy between ALS motor neurons and glia.
These studies pave the way for a number of promising new avenues in ALS research. They provide an assay for the identification of the toxic factor(s) released by glial cells, and possibly the discovery of small molecules that protect neurons from their action. They also suggest that human ES cell lines carrying genes from ALS patients, created either by transgenic methods or by somatic cell nuclear transplantation, may provide the first real opportunity to study the degeneration of human motor neurons in ALS.
Article title: Non–cell autonomous effect of glia on motor neurons in an embryonic stem cell–based ALS model
