ALS Research Briefs: Role of Astrocytes in ALS

Scientists continue to work at uncovering the biological mechanisms underlying amyotrophic lateral sclerosis (ALS). One area of intense study involves the potential role of central nervous system support cells called astrocytes

Astrocytes normally protect motor neurons (muscle-controlling nerve cells that die in ALS), but some studies have demonstrated that astrocytes can turn toxic and become harmful to motor neurons as ALS progresses. Determining the circumstances under which this happens — or doesn't happen — may provide scientists with important clues about ALS that may be used to identify markers of disease progression and potential biological targets for therapy development.

Read below to learn about the results from two new studies that shed additional light on astrocyte involvement in ALS.

Astrocytes with SOD1 mutation toxic to motor neurons

In a group of experiments conducted in both cell culture and in the SOD1 ALS research mouse model, researchers found that complex interactions between motor neurons and astrocytes affect the disease process in ALS that’s caused by mutations in the SOD1 gene.

The researchers noted that, when astrocytes carry an ALS-causing SOD1 mutation, the mutation affects gene activity (expression) not only in the astrocytes but also in neighboring motor neurons. Changes occur in the activity of two types of genes: those that carry the genetic code for production of cell surface proteins, and those that are involved in cellular response to stress or injury. These changes appear to contribute to "profoundly disrupted" communication between astrocytes and motor neurons and to disrupt an interconnected network of pathways, including the TGF-beta signaling pathway. Ultimately, the changes in gene activity lead to motor neuron loss.

If confirmed, data from the study could help scientists identify potential biological targets for use in therapy development.

The research team, led by Tom Maniatis at Columbia University Medical Center in New York, published its results online Feb. 6, 2013, in Proceedings of the National Academy of Sciences. Read the full report, for a fee: Intricate Interplay Between Astrocytes and Motor Neurons in ALS.

Astrocytes with TDP43 mutation not toxic to motor neurons

In another study, investigators generated astrocytes from human induced pluripotent stem cells, or iPSCs, carrying an ALS-causing mutation in the gene for TDP43. (An iPSC is an adult cell that has been "reprogrammed" back to an immature stem-cell-like state, after which it can be prompted to develop into any type of cell in the body.)

They found that astrocytes carrying the mutation were at significantly greater risk of death than were control (nonmutated) astrocytes, but that they did not appear to be directly toxic to either normal motor neurons or those carrying the TDP43 mutation when grown (cultured) with them in a dish. (Loss of astrocytes is harmful to motor neurons, but the astrocyte abnormality itself did not directly affect motor neurons in these experiments.)

The data from these experiments suggest that:

  • changes in astrocyte survival and behavior in ALS might be directly related to mutations in these cells themselves, rather than a consequence of motor neuron loss; and
  • a potential difference exists between astrocyte-motor neuron interactions — at least in cell culture experiments — depending on whether the mutation is in TDP43 or SOD1.

TDP43 protein is found in inclusions in the motor neurons of people with sporadic ALS, ALS with dementia, and non-SOD1-related familial ALS, but not in inclusions from individuals with SOD1-related familial ALS. Thus, understanding whether TDP43-mutation-carrying astrocytes have a comparable neurotoxic effect to SOD1-mutation-carrying astrocytes is of great interest, the study authors wrote.

The research team, led by Siddharthan Chandran at the University of Edinburgh, United Kingdom, published its results online Feb. 11, 2013, in Proceedings of the National Academy of Sciences. The full report can be read for free: Astrocyte Pathology and the Absence of Non-Cell Autonomy in an Induced Pluripotent Stem cell Model of TDP-43 Proteinopathy.

Different types of ALS?

Learning about astrocyte involvement — and other potential contributors to the disease process — in different types of ALS is important when it comes to finding treatments.

Some research has suggested that familialALS caused by mutations in the SOD1 gene may be different from sporadic ALS and other familial forms of the disease. 

There also is increasing focus in the ALS research community on the fact that ALS demonstrates a great deal of variability (heterogeneity) from one person to the next. Time and type of onset, rate and pattern of progression, and other aspects of the disease vary widely among individuals.

This variability in ALS has implications for drug testing and therapy development. In clinical trials, it's important for investigators to test experimental therapies in participants who are as similar to each other as possible. Ultimately, it may be found that different people require different treatments, depending on the biological processes driving the disease.

For more information

To learn more about astrocytes in ALS, see:

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