When good cells go bad, as they seem to do in ALS, you have to ask the same questions distraught parents sometimes ask about wayward children: Is the problem strictly internal? Are outside influences also to blame? And if they are, what can be done about them?
As far back as 2003, Don Cleveland and colleagues at the University of California-San Diego showed that, in ALS, outside influences in the cellular neighborhood in the nervous system matter.
In their experiments, mice with an ALS-causing genetic mutation in the SOD1 gene were saved from the expected degeneration of their motor neurons (movement-controlling nerve cells that are lost in ALS) if they had enough non-nerve cells without the disease-causing mutation surrounding these neurons. It was as if these healthy cells protected the sick ones, even though the ailing cells harbored the factor that caused the disease.
Last June, Cleveland’s group zeroed in on a particular cell type, the microglia, immune-system cells that live in the brain and spinal cord. They aren’t neurons, but they sense their surroundings and swing into defensive action when they sense that neurons are in trouble. When activated, they can produce helpful proteins, but they also kick off the immune system’s inflammatory response, which can cause collateral damage.
|In ALS, researchers believe, distress signals from motor neurons activate microglia, which can then cause further damage
When Cleveland’s group bred mice that produced mutant SOD1 protein in their nerve cells and elsewhere, but hardly at all in their microglia, they lived an average of 99 days longer than mice that produced mutant SOD1 in all their cells, including their microglia, leading the investigators to conclude that relatively healthy microglia benefit animals destined to develop SOD1-related ALS.
Interestingly, limiting this damage didn’t change the onset or the early course of the ALS-like disease that affected these mice. Its effect came in prolonging late-stage ALS and survival.
The researchers concluded that initiation of the ALS disease process (at least in this type of ALS) probably requires damage to motor neurons and maybe other types of cells, but that activated microglia intensify the disease and might be a good target for therapies.
In October, Stanley H. Appel, an MDA research grantee who directs the MDA/ALS Center at Methodist Neurological Institute in Houston, and colleagues, conducted a set of experiments that led to similar conclusions.
These investigators bred mice that had not only an ALS-causing SOD1 mutation, but also lacked an immune system. Against this immunologic clean slate, Appel’s group added either normal immune-system cells, from normal mouse bone marrow; or abnormal immune-system cells, carrying an SOD1 mutation. Among the immune cells were microglia.
As in Cleveland’s experiments, Appel’s experiments showed that mice destined to develop ALS fared better if their microglia didn’t carry an SOD1 mutation. (Appel says those microglia are harder to activate than those with an SOD1 mutation.) Of course, major questions remain. Targeting microglia may be a good idea for therapy, but what kind of therapy? Destroying microglia or keeping them inactive might prevent much of the inflammatory response that clearly contributes to progression of the disease, but it would also eliminate the beneficial effects of these cells. Microglia release neurotrophic (nerve-nourishing) proteins, and they stimulate clearance of potentially toxic substances in the area by cells called astrocytes.
A second burning question is, do findings in the SOD1 mouse model translate into human ALS, when SOD1-related ALS accounts for only 1 percent to 3 percent of human cases of the disease?
Appel says they probably do, because he believes the issue is whether or not microglia are activated. Cells carrying the SOD1 mutation are more active than those without it, he says, and they secrete high levels of compounds that participate in inflammatory reactions, such as TNF-alpha and interleukins.
“It’s clear that all the inflammatory constituents present in the mouse model are present in human sporadic ALS,” Appel says, concluding that “it’s tempting to speculate that microglia and immune cells could be playing a role in man as they do in the mouse model.”
He says that in both mouse and human ALS, there are clumps of proteins and inflammation in the nervous system. In the mouse, clumps of abnormal SOD1 protein molecules are likely involved in activating microglia. In humans, the proteins that clump are different, but the result may be the same.
“In human ALS,” he says, “there are also many aggregated proteins [though not usually SOD1] in motor neurons, so it’s not too much of a leap of faith to assume that such aggregated [clumped] proteins could be released from motor neurons, activate microglia, and amplify the injury to motor neurons. Then some of the same concepts involved in the animal model would be involved in human sporadic disease, with the major difference being a difference in the specific protein aggregates initiating the microglial activation in the mouse versus man.”
Appel says he knows these thoughts are speculative, but, he notes, “our own data and the data of our colleagues seem to be pointing in this direction.” (In December, his group’s analysis of a pilot trial of bone marrow transplantation in people with ALS was nearing completion.)
Critics say applying findings from the SOD1 mouse to human ALS is like looking under a lamppost for dropped keys just because that’s where the best light is. To them, Appel responds, “We may be looking under a lamppost, but I’d say, ‘Show me another light.’ I want to find the keys as much as anyone else. Let’s take every lead.”