Wednesday, 3 December 2008

ALS Model from Human ESCs I

Motor neurons derived from human embryonic stem cells provide insight into ALS Wednesday, 03 December 2008 Two new research studies use motor neurons derived from human embryonic stem cells (hESCs) to demonstrate that multiple toxic pathways contribute to the devastating degeneration associated with Amyotrophic Lateral Sclerosis (ALS) and that protective therapeutics will need to oppose the disease on multiple fronts. The separate studies, published by Cell Press in the December issue of the journal Cell Stem Cell, also underscore the validity of using human stem cells to both identify new strategies for protecting motor neurons and screen potential therapeutics. ALS, also known as Lou Gehrig's disease, is characterized by death of motor neurons in the brain and spinal cord, muscle atrophy and fatal paralysis. Previous research has shown that mutations in the widely expressed enzyme superoxide dismutase I gene (SOD1) can lead to ALS. Work with animal models expressing mutant SOD1 has provided valuable insight into the complex metabolic pathways involved in disease pathogenesis and has indicated that non-neuronal support cells, called astrocytes, contribute to disease progression. However, drugs that have successfully protected motor neurons in mouse models have not proven useful in human clinical trials. "There is an urgent need for new ALS models that have the potential to be translated into clinical trials that could, at a minimum, be used in conjunction with mouse models to verify targets and drugs," explains Dr. Fred H. Gage from The Salk Institute for Biological Studies. To investigate the contribution of astrocytes to human motor neuron degeneration, Dr. Gage and colleague Dr. Corol Marchetto co-cultured hESC-derived motor neurons with human primary astrocytes expressing mutated SOD1. They found that the conditions were selectively toxic for the healthy motor neurons. The toxicity was related to an inflammatory response initiated by the astrocytes and the production of damaging reactive oxygen species (ROS). Importantly, pharmacological blockade of ROS production rescued the motor neurons from mutant SOD1 toxicity. A separate study led by Dr. Kevin C. Eggan and colleague Paolo Di Giorgio from The Harvard Stem Cell Institute also used hESC-derived motor neurons to examine the toxic effects of astrocytes expressing mutant SOD1. "We examined the utility of specific neuronal subtypes, including spinal motor neurons, derived from hESCs for investigating the disease mechanisms leading to ALS and the identification of small molecules that can counteract their effects," says Dr. Eggan. Using a sophisticated genetic screening technique, the researchers identified specific genes that were expressed in the mutant astrocytes. One molecule, prostaglandin D2, could by itself induce a loss of motor neurons similar to that seen in co-culture with SOD1 mutant astrocytes. The group went on to show that blockade of the prostaglandin D2 receptor rescued motor neurons from the astrocyte-induced toxicity. The findings of both studies confirm the toxic interactions between mutant SOD1-expressing astrocytes and motor neuron as a valid target for development and testing of ALS therapeutics. Further, the research shows that hESC-based systems are an invaluable research tool for disease modelling with specific cell types. References: Human Embryonic Stem Cell-Derived Motor Neurons Are Sensitive to the Toxic Effect of Glial Cells Carrying an ALS-Causing Mutation Francesco Paolo Di Giorgio, Gabriella L. Boulting, Samuel Bobrowicz and Kevin C. Eggan Cell Stem Cell, Volume 3, Issue 6, 637-648, 4 December 2008 Non-Cell-Autonomous Effect of Human SOD1G37R Astrocytes on Motor Neurons Derived from Human Embryonic Stem Cells Maria C.N. Marchetto, Alysson R. Muotri, Yangling Mu, Alan M. Smith, Gabriela G. Cezar and Fred H. Gage Cell Stem Cell, Volume 3, Issue 6, 649-657, 4 December 2008 See also: ALS Model from Human ESCs II A novel human stem cell-based model of ALS opens doors for rapid drug screening CellNEWS - Wednesday, 03 December 2008 ......... ZenMaster

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