Geriatric Astrocytes Fail Motor Neurons in ALS Model

Older people can get a boost from the vigor and vitality of youngsters. Aging cells may enjoy a similar benefit. Motor neurons survive longer when surrounded by young astrocytes, according to a paper in press in Neurobiology of Aging. In contrast, older astrocytes make a feeble support crew, report first author Melanie Das and senior author Clive Svendsen of the Cedars-Sinai Medical Center in Los Angeles. Furthermore, older astrocytes harboring mutations that cause amyotrophic lateral sclerosis perform even worse. Das and Svendsen have identified a potential rejuvenating elixir. They found that glial-derived neurotrophic factor (GDNF) helped older astrocytes protect motor neurons. Svendsen’s group plans to generate GDNF-producing astrocytes from stem cells and test them in normally aging rats and ALS mouse models.

The Old Guard Falters.

Motor neurons (green) co-cultured for seven days with young astrocytes (top) survive better than those supported by old astrocytes (bottom), even when the astrocytes express mutant SOD1. (Blue indicates nuclei of both cell types.) [Image courtesy of Melanie Das, Cedars-Sinai Medical Center.]

Astrocytes from ALS model animals expressing mutant human superoxide dismutase 1 are well known to poison motor neurons in co-culture (see Apr 2007 news story). Das found this was not the case if the astrocytes came from 2-day-old rat pups (see image at left). The same was true for wild-type astrocytes. Young cells supported motor neurons much better than did glia from 5-month-old mice. What was different about the older astrocytes? Das saw they had more DNA damage than the young cells. While this is often a sign of cellular senescence, these astrocytes stuck around.

To look for astrocyte senescence in vivo, Das examined spinal cords from middle-aged and old wild-type mice, and from end-stage mSOD1 animals. Astrocytes from 150-day-old wild-type mice appeared normal. Astrocytes from 300-day-old wild-type mice and 150-day-old mSOD1 animals, which is about as long as these mice survive, expressed markers of senescence, including β-galactosidase and tumor suppressors p16 and p21. “Senescence usually occurs when a cell is stressed out and accumulating damage,” Das said. The mSOD1 astrocytes appeared to be on an accelerated aging course. Das suggested that they are getting overworked.

Might there be something that could nurture these astrocytes? Previously, the Svendsen lab found that GDNF protects motor neurons in an mSOD1 rat model (Suzuki et al., 2007). When Das treated astrocytes from aged wild-type rats and end-stage mSOD1 mice with GDNF for a week, the cells appeared to rejuvenate. They dropped production of the senescence marker p21, and also of the pro-inflammatory cytokine IL-6. Moreover, astrocytes primed with GDNF kept motor neurons alive in co-culture longer than untreated astrocytes.

The researchers are still trying to figure out how mSOD1 influences astrocyte health and activity. Recently, scientists reported that mutant astrocytes express too much of a sodium/potassium pump (see Oct 2014 news story). It is too early to say if GDNF affects that pump, or if the growth factor and pump are part of parallel pathways that affect astrocyte health, Das said.

Das and Svendsen hope that GDNF-producing cells derived from induced pluripotent stem cells could benefit both astrocytes and motor neurons in people with familial ALS due to SOD1 mutations. If aged astrocytes also falter in people with other forms of ALS, such a treatment could benefit them as well, Das speculated.—Amber Dance

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References

News Citations

  1. Glia—Absolving Neurons of Motor Neuron Disease
  2. In ALS, Astrocytes Use Ion Pump to Blast Motor Neurons

Paper Citations

  1. Suzuki M, McHugh J, Tork C, Shelley B, Klein SM, Aebischer P, Svendsen CN. GDNF secreting human neural progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial ALS. PLoS One. 2007;2(8):e689. PubMed.

Further Reading

Papers

  1. Bhat R, Crowe EP, Bitto A, Moh M, Katsetos CD, Garcia FU, Johnson FB, Trojanowski JQ, Sell C, Torres C. Astrocyte senescence as a component of Alzheimer's disease. PLoS One. 2012;7(9):e45069. PubMed.
  2. Klein SM, Behrstock S, McHugh J, Hoffmann K, Wallace K, Suzuki M, Aebischer P, Svendsen CN. GDNF delivery using human neural progenitor cells in a rat model of ALS. Hum Gene Ther. 2005 Apr;16(4):509-21. PubMed.
  3. Li W, Brakefield D, Pan Y, Hunter D, Myckatyn TM, Parsadanian A. Muscle-derived but not centrally derived transgene GDNF is neuroprotective in G93A-SOD1 mouse model of ALS. Exp Neurol. 2007 Feb;203(2):457-71. PubMed.
  4. Bohn MC. Motoneurons crave glial cell line-derived neurotrophic factor. Exp Neurol. 2004 Dec;190(2):263-75. PubMed.

Primary Papers

  1. Das MM, Svendsen CN. Astrocytes show reduced support of motor neurons with aging that is accelerated in a rodent model of ALS. Neurobiol Aging. 2015 Feb;36(2):1130-9. Epub 2014 Sep 28 PubMed.

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