Is it time to redefine ALS? As described in a companion story, there is growing evidence that ALS is more than simply a disease of upper and lower motor neurons. Cytoplasmic inclusions of the protein TDP-43, a hallmark of both familial and sporadic ALS, are widespread in the brains of patients, indicating that the disease damages other neurons and non-neuronal cells. This is consistent with data from animal models based on expression of mutant superoxide dismutase 1 (SOD1), a rare cause of familial ALS. Five years ago, Don Cleveland and colleagues at the University of California, San Diego, showed that expressing mutant SOD1 in glia is sufficient to induce ALS-like pathology in mice and can speed up progression, and also that wild-type non-neuronal cells can protect neurons expressing the SOD1 mutation. Both observations showed that the disease does not simply begin and end with motor neurons (see ARF related news story). Now, Cleveland and colleagues have addressed this concept in a slightly different way. In this week’s PNAS online, they report that cells other than motor neurons can postpone the time of onset of disease. The work strengthens the idea that ALS is not a cell-autonomous disease of motor neurons.

There are indications that onset and progression of disease in SOD1 mouse models are independent. Reducing expression of SOD1 in microglia and astrocytes slows progression, for example, but has no effect on time of onset. In contrast, reducing SOD1 in motor neurons postpones onset but has little effect on progression. What is not clear is whether onset is solely determined by the motor neurons, or whether other cell types can influence it. To address this, Cleveland, Larry Goldstein—also at UCSD—and colleagues used chimeric animals in which motor neurons always express mutant SOD1 (G37R mutation), while other neurons and non-neuronal cells are a mixture of mutant and wild-type. If onset is simply a function of SOD1 in motor neurons, then all of the various chimeras should show disease onset at the same age. That is not what first author Koji Yamanaka and colleagues found.

Yamanaka and colleagues made chimeras by mixing early embryonic (morula) cells from mutant SOD1 mice with morula cells deficient in the Olig1 and Olig2 transcription factors. Though the Olig transcription factors are essential for motor neuron viability, chimeric mice can survive because they also contain Olig-positive cells from the SOD mutant morulas. In fact, the mice obtained all expressed mutant SOD in their motor neurons, suggesting no contribution to that neuronal pool from wild-type cells in the chimeras.

The chimeras had fewer motor neurons than normal, which the authors explain by the presence of Olig-/- progenitor cells early in development rather than toxicity of mutant SOD (control chimeras made from wild-type SOD morulas were similarly lacking motor neurons). However, the chimeras did not have early onset motor neuron disease. Of seven chimeras studied, four showed no signs of disease onset up to 239 days, which is well beyond the average age of onset for SOD1 mutant mice of 160 days. Of the remaining three mice, one showed onset at 192 days, one died of unknown causes at 125 days, and the last was used for histological analysis at day 65. The four disease-free mice also did not exhibit the normal weight loss that is typical at disease onset. “Thus, these animals exhibited no signs of the onset of ALS despite having all of their motor neurons mutant for SOD1,” write the authors.

The work suggests that other protective cells must be at play in determining onset of ALS. What those cells are is unclear. The authors rule out oligodendrocytes since there are no wild-type oligodendrocytes in the chimeras to protect the motor neurons. Similarly, previous work has shown that glia and astrocytes have no effect on disease onset. The authors suggest interneurons, the myelinating Schwann cells of the periphery, and the endothelial cells of the vasculature may be worth investigating. “In any event, the cumulative evidence supports the hypothesis that it is ALS-linked mutant SOD1 within multiple cell types that, in collaboration with damage directly within motor neurons, drives non-cell-autonomous onset of motor neurodegeneration,” write the authors.

Whether multiple cell types promote disease onset in non-SOD1 ALS cases remains to be seen. TDP-43 pathology is found in both neurons and glia, suggesting that pathology in many, if not most, ALS cases may not be cell-autonomous. Making mutant TDP-43 chimeras may help solve that question. Numerous labs are working on making TDP-43 models.—Tom Fagan


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News Citations

  1. Research Brief: Redefining ALS—Time to Think Laterally?
  2. ALS—Is It the Neurons or the Glia?

Further Reading

Primary Papers

  1. . Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice. Proc Natl Acad Sci U S A. 2008 May 27;105(21):7594-9. PubMed.