Is Fixing Motor Neurons the Only Path to Treating ALS?

by Margaret Wahl on Sun, 2009-02-01 13:47

Some studies suggest that motor neurons, even when healthy, can be killed by toxic neighbors. If so, converting these “sharks” to “dolphins” might slow the pace of ALS.

Since the earliest descriptions of ALS, it’s been noted that progressive muscle atrophy (shrinkage) and weakness are hallmarks of the disease. For decades the assumption has been that the muscle degeneration results from the loss of muscle-stimulating nerve cells in the spinal cord and brain, known as motor neurons.

But that assumption has been questioned in recent years, with several scientists finding that other types of cells, such as nervous-system support cells called glia, and even muscle itself, may make significant contributions to the disease.

If these other cells do contribute to the disease process, that would be good news, because glia and muscle cells may be easier treatment targets than motor neurons.

Microglia add fuel to fire

In 2006, Don Cleveland and colleagues at the University of California-San Diego showed that, in ALS, outside influences from cells in the nervous-system neighborhood do matter. (See “Outside Agitators,” ALS Newsmagazine, February 2007.) Cleveland’s group focused on the role of microglia, a type of glial cell in the nervous system whose normal job is to protect neurons from microbes that threaten their survival.

The group’s experiments in mice led them to conclude that initiation of the ALS disease process probably requires damage to motor neurons but that activated microglia intensify the disease.

What role do astrocytes play?

Other groups have focused their attention on astrocytes, another type of glial cell. Once thought to be merely “glue” providing structural support, these star-shaped cells are now known to play additional roles in the neuronal environment, such as cleaning up excess glutamate, which can be toxic. But what, if any, contribution do they make in ALS?

On Dec. 10, investigators at the University of Wisconsin-Madison coordinated by Jeffrey Johnson published a paper in the Journal of Neuroscience that showed treating astrocytes alone can delay disease onset and extend survival in mice with an ALS-like disorder.

(Note: these experimental mice, the most common animal “model” of ALS, carry mutated genes for the SOD1 protein. Some 1 percent to 3 percent of human ALS cases can be attributed to SOD1 mutations. At present, no exact mouse model exists for the most common form of ALS because the cause of the disease is unknown.)

The benefit in the Johnson group’s experiments in ALS mice was brought about by increasing astrocyte production of a protective protein called NRF2.

Two other research teams published astrocyte experimental results in the Dec. 4 issue of Cell Stem Cell.

Maria Marchetto at the Salk Institute for Biological Studies in La Jolla, Calif., and colleagues, maintained healthy human motor neurons in a culture dish with normal human astrocytes, or with human astrocytes carrying an ALS-causing mutation. The group found that only the motor neurons that were mixed with the mutation-containing astrocytes died. This toxic effect could be prevented by treating the astrocytes with the antioxidant apocynin, the group found.

Francesco Paolo Di Giorgio and colleagues at Harvard University reported results at the same time from similar experiments. This group of scientists also found that mouse astrocytes carrying an ALS-causing mutation killed healthy human motor neurons in a culture dish.

They determined that the poisonous effect of the mutation-carrying glial cells was at least in part caused by their production of a chemical called prostaglandin D2. Blocking this compound provided partial but significant protection to the motor neurons in the dish.

Important or not?

Many experts are skeptical about major non-neuronal contributions to ALS. Among the doubters of a primary role for non-neurons is Jeffrey Elliott, an MDA grantee at The University of Texas Southwestern Medical Center in Dallas. A study published by Elliott and colleagues in the Journal of Neuroscience in 2000 concluded that, while the presence in mice of mutant SOD1 in astrocytes alone caused significant changes to the astrocytes, it was not sufficient to kill motor neurons or produce an ALS-like disease.

Dutch researchers published a complementary paper in 2008 in the same journal showing that production of mutated SOD1 protein in neurons alone was enough to produce an ALS-like disease in mice.

Together, these two studies lead to a conclusion that the presence of mutated SOD1 protein solely in astrocytes is neither sufficient nor necessary to cause ALS in mice, although neither study rules out a potential contribution from these cells.

Elliott says that, although he believes SOD1-related ALS is neuronally based, involvement of other cell types “may impact the disease.”

Does muscle matter?

In another recent study, MDA grantee Antonio Musaro at the University of Rome coordinated a research team that determined that mice carrying an SOD1 mutation solely in their muscle cells developed severe muscle wasting despite the presence of unharmed, healthy motor neurons.

But, in an earlier study, lowering mutant SOD1 levels in muscle tissue alone failed to improve survival or affect disease onset. Enhancing muscle mass and strength in the mice likewise had no benefit.

Experiments hard to compare

Unfortunately, experiments differ so widely in the questions asked and techniques employed that direct comparisons are impossible.

For instance, investigators recently examining the contribution of glial-cell abnormalities to motor-neuron degeneration note that their experiments were conducted using human motor neurons and may therefore be better at mimicking human ALS than experiments conducted in rodents.

Elliott, however, has a less enthusiastic view of studies conducted in laboratory dishes rather than animals, whether or not they involve human cells. “Cells do not get ALS or weakness,” he says, “so one must be cautious about over-interpreting such results.”

Several studies, some of which are listed below, have been conducted in rodents and in laboratory dishes to probe the role of motor neurons versus other cell types in ALS. Non-neuronal cells probably exacerbate the disease and would be easier to reach with therapies than motor neurons. But the benefits of treating them in patients remain uncertain.


Gong and colleagues
Journal of Neuroscience
Jan. 15, 2000
SOD1 mutation in astrocytes alone did not cause motor neuron degeneration in mice.
Boillee and colleagues
June 2, 2006
Levels of mutant SOD1 in motor neurons was a primary determinant of disease onset and early phase of progression in mice; reduction of mutant SOD1 levels in microglial cells had little effect on early disease but sharply slowed later progression.
Miller and colleagues
Proceedings of the National Academy of Sciences
Dec. 19, 2006
Diminishing mutant SOD1 in muscle did not affect motor neuron disease onset or survival in mice; enhancing muscle mass provided no benefit with respect to disease onset or progression.
Nagai and colleagues
Nature Neuroscience
April 15, 2007
Diminishing mutant SOD1 level in muscle did not affect onset or survival of ALS in mice.
Yamanaka and colleagues
Nature Neuroscience
Feb. 3, 2008
Diminished levels of mutant SOD1 in astrocytes alone did not affect disease onset but sharply slowed disease progression.
Jaarsma and colleagues
Journal of Neuroscience
Feb. 27, 2008
Mutated SOD1 genes in motor neurons alone were sufficient to cause ALS-like disease in mice.
Lepore and colleagues
Experimental Neurology
March 7, 2008
Proliferation of astrocytes in mice with an SOD1 mutation did not play a significant role in their motor neuron disease.
Dobrowolny and colleagues
Cell Metabolism
November 2008
Mice with mutant SOD1 only in skeletal muscle developed muscle atrophy, reduction in strength and other abnormalities.
DiGiorgio and colleagues
Cell Stem Cell
Dec. 4, 2008
Astrocytes with an SOD1 mutation had toxic effect on human motor neurons in a laboratory container.
Marchetto and colleagues
Cell Stem Cell
Dec. 4, 2008
Astrocytes with an SOD1 mutation reduced survival of healthy motor neurons in a laboratory dish with them by 50 percent.
Vargas and colleagues
Journal of Neuroscience
Dec. 10, 2008
Boosting protective pathway in astrocytes protected motor neurons in ALS mice.

Non-neuronal neighbors could be easier to reach and treat than neurons

If abnormalities in glial cells or muscle fibers make a major contribution to ALS progression or severity, whether or not they can actually cause the disease, treating them could retard progression or reduce severity, and that would be good news.

Motor neurons are hard to reach with therapies, because they’re surrounded by a protective barrier that keeps most substances out of the spinal cord and brain. They’re also delicate, and, once injured, they can’t divide or replace themselves the way many other cell types, including glia, can. Finally, they control movement via long fibers (axons) that extend from the spinal cord to muscles. These can take months to develop and must reach their targets precisely.

Glial cells are also inside the barrier that surrounds the central nervous system, but they divide often, and sick ones can be replaced with healthy ones. And although they communicate with neighboring cells, they don’t do so via long fibers.

Muscles are outside the nervous system, and they’re fairly easy to reach with therapeutic substances. And unlike neurons, muscle fibers can repair themselves, although not as readily as some other cell types do. Replacing damaged muscle fibers, though difficult, is being seriously considered as a strategy for treating muscle diseases and might confer some benefit to ALS patients.

Of more immediate importance, therapeutic genes injected into muscles can, depending on how they’re packaged, travel up nerve fibers into neurons in the spinal cord. MDA grantee Brian Kaspar, at Nationwide Children’s Hospital in Columbus, Ohio, is working on delivering genes for proteins such as insulin-like growth factor 1 (IGF1) to skeletal muscle. IGF1 and other so-called trophic (nourishing) factors may have beneficial effects in nerve and/or muscle cells.

Margaret Wahl
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