Human Cell Assay for Amyotrophic Lateral Sclerosis (ALS)
Inventors: Maria C.N. Marchetto and Fred H. Gage
Potential Uses: Drug Discovery and Development, Amyotrophic Lateral Sclerosis, ALS, Neurodegenerative disease
Figure 1. hESC-Derived Neuronal Cocultures with Human Astrocytes. Human primary astrocytes were infected with Lentivirus SOD1WT or Lentivirus SOD1G37R for SOD1 (wild-type or mutated) overexpression. hESCs were differentiated into motor neuron precursors (rosettes), gently dissociated, and plated on two different glial monolayers. The cocultures were then infected with LentiHb9::GFP and carried out for three more weeks.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative adult disease characterized by fatal paralysis in both the brain and spinal cord motor neurons due to motor neuron death. ALS can be induced by inherited mutations in the gene encoding the ubiquitously expressed enzyme superoxide dismutase (SOD1). Currently, there is only one FDA-approved treatment for ALS, riluzole, and it only extends the course of the disease for two months. There is an urgent need for new ALS models that have the potential to be translated into clinical trials and could, at a minimum, be used in conjunction with the murine models to verify targets and drugs. Recent research using chimeric mice with a mutated SOD1 in either astrocytes or microglia has shown the non-cell-autonomous nature of ALS; the mutated cells reduced motor neuron survival.
In an interest to develop a new model and to uncover the contribution of astrocytes to human motor neuron degeneration, we developed a system where we co-cultured hESC-derived motor neurons with human primary astrocytes expressing mutated SOD1 (Figure 1). Using this assay, we confirmed the role of astrocytes in ALS disease, as motor neuron numbers decreased about 50% in the presence of mutant SOD1-expressing astrocytes. Moreover, the toxicity seemed to be restricted to the motor neuron subpopulation, with no effects on other neuronal subtypes. Lastly, in individual experiments with several different antioxidants as well as with apocynin, we were able to prevent the loss of motor neurons caused by co-culture with SOD1-mutated astrocytes. Taken together, these results provide a new model for use as an assay for ALS drug screening.
Patent Status: U.S. Provisional Patent Application filed as 61/119700
Publications: Cell Stem Cell 3, 649 - 657, December 4, 2008
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