31 May, 2010. Motor neuron disease progresses from full health to paralysis and death in a matter of years, but researchers know little about the changes that happen along the way. Two recent papers provide more information about how motor neuron disease progresses in rodents. In the June Journal of Neuropathology and Experimental Neurology, researchers present a potential new model for amyotrophic lateral sclerosis (ALS): a mouse with a mutation in the cholesterol homeostasis pathway that suggests cholesterol metabolism and neuroinflammation may be tied together in some way. And in a paper posted online by the journal Neuroscience on May 12, scientists report that activation transfer factor-3 (ATF-3) is a marker for distressed neurons and glia as disease progresses in a rat model for the disease.

Cholesterol Metabolism Meets Neurodegeneration
The ALS field is in dire need of new animal models (see ARF Live Discussion). Jan-Åke Gustafsson and colleagues at the Karolinska Institute in Stockholm, Sweden, developed a potential model as they were researching mice lacking liver X receptor β (LXRβ), a nuclear receptor that regulates lipid metabolism and inflammation. They discovered impaired motor coordination and motor neuron loss in the knockout animals (Andersson et al., 2005). In the current J Neuropath Exp Neurol paper, Gustafsson further explores disease progression in this model. The joint first authors are Paolo Bigini of the Mario Negri Institute for Pharmacological Research in Milan, Italy, and Knut Steffensen of the Karolinska Institute.

Over the course of two years, the researchers observed symptoms in the LXRβ knockout mice and compared them to wild-type animals. The knockouts failed to gain weight like normal animals. By 27 weeks, they weighed 33 grams and were lagging behind the 35-gram control animals. Over the ensuing months, the LXRβ knockout animals never topped 35 grams, while the wild-type mice weighed more than 40 grams by 100 weeks.

To analyze motor symptoms, the scientists tested the mice for grip strength and for balance on the rotarod. At an age of 45 weeks, the LXRBβ knockout mice started to struggle on the latter, and by week 100 could only hang onto the device for 50 seconds. Wild-type animals had some decrease in their times, but stayed above 120 seconds throughout the study period. In the knockouts, grip strength dropped from 115 grams at week 30, to 79 grams at week 60. During the same time period, control animals actually increased in grip strength, from 115 grams to 144 grams.

The researchers sacrificed some of their study animals at three, 10, and 24 months to examine them for neural pathology. At three months, the knockouts had the same numbers of neurons and neuromuscular junctions (NMJs) as controls. By 10 months, knockouts had fewer cholinergic neurons but maintained NMJs. At 24 months, the researchers observed loss of both spinal neurons and NMJs in the knockout animals.

Pre-symptomatic knockout animals evinced accumulation of cholesterol and inflammation in the spinal cord. Using mRNA analysis, Gustafsson and colleagues also observed an increase in transcription of inflammation-linked genes in the knockout mice. They suggest that cholesterol metabolism and neuroinflammation make these animals particularly susceptible to motor neuron degeneration, and that the LXRβ knockout mouse could be a valuable model for ALS.

Unlike the current top ALS model—mice expressing mutant human superoxide dismutase 1 (SOD1)—the LXRβ knockout animals lack some basic characteristics of the disease. They do not develop paralysis, nor is their lifespan shortened. They show less motor neuron loss than autopsy tissues from people who died of ALS. However, the authors suggest, they may be useful as an animal model that is unusually susceptible to motor neuron disease. Scientists suspect that environmental factors may interact with genetics to produce sporadic ALS. To test environmental agents, researchers might expose them to LXRβ knockout mice, then look for an increase in disease.

Stressed-Out Nerves
In the Neuroscience paper, researchers from Queen Mary University of London, UK, followed a new marker, ATF-3, in rats overexpressing human SOD1-G93A. First author Andrea Malaspina led the work with senior author John Priestley. ATF-3 is a cellular distress marker common to both neurons and glia, and the researchers suspected it would provide clues about different cell types as they succumb to disease. They used immunohistochemistry to follow ATF-3 from the pre-symptomatic stage to end stage.

At 10 weeks of age, SOD1 rats have not yet begun to show symptoms of disease, but the scientists observed ATF-3 in dorsal root ganglia (DRG) neurons as well as S-100 positive Schwann cells. Control, wild-type animals evinced very little ATF-3 staining.

The researchers sacrificed end-stage animals when they had either lost one-quarter of their body weight or were unable to transition from lying on their sides to being upright. In these animals, Malaspina and colleagues observed ATF-3 in DRG neurons, Schwann cells and lumbar spinal cord neurons. Age-matched wild-type animals did not exhibit this spinal cord staining.

ATF-3, and thus presumably cell stress, began in non-neuronal cells and transitioned to neurons, the authors note. They conclude that ALS may begin in the periphery of the central nervous system, and the early stages may also affect DRG neurons. However, they point out, the current study does not tell whether ATF-3 activation is helpful or harmful. And without human data, it is not possible to say whether ATF-3 will be a useful biomarker to track the disease in people.—Amber Dance


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Webinar Citations

  1. Mice on Trial? Issues in the Design of Drug Studies

Paper Citations

  1. . Inactivation of liver X receptor beta leads to adult-onset motor neuron degeneration in male mice. Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3857-62. PubMed.

Further Reading


  1. . Ubiquilin modifies TDP-43 toxicity in a Drosophila model of amyotrophic lateral sclerosis (ALS). J Biol Chem. 2010 Apr 9;285(15):11068-72. PubMed.
  2. . Pluripotent stem cells in neurodegenerative and neurodevelopmental diseases. Hum Mol Genet. 2010 Apr 15;19(R1):R71-6. PubMed.
  3. . Lipid rafts: keys to neurodegeneration. Brain Res Bull. 2010 Apr 29;82(1-2):7-17. PubMed.
  4. . CSF glial markers correlate with survival in amyotrophic lateral sclerosis. Neurology. 2010 Mar 23;74(12):982-7. PubMed.
  5. . Decreased level of 5-methyltetrahydrofolate: a potential biomarker for pre-symptomatic amyotrophic lateral sclerosis. J Neurol Sci. 2010 Jun 15;293(1-2):102-5. PubMed.
  6. . Immunoreactivity of the phosphorylated axonal neurofilament H subunit (pNF-H) in blood of ALS model rodents and ALS patients: evaluation of blood pNF-H as a potential ALS biomarker. J Neurochem. 2009 Dec;111(5):1182-91. PubMed.

Primary Papers

  1. . Activation transcription factor-3 activation and the development of spinal cord degeneration in a rat model of amyotrophic lateral sclerosis. Neuroscience. 2010 Aug 25;169(2):812-27. PubMed.
  2. . Neuropathologic and biochemical changes during disease progression in liver X receptor beta-/- mice, a model of adult neuron disease. J Neuropathol Exp Neurol. 2010 Jun;69(6):593-605. PubMed.