Two new research studies use motor neurons derived from human embryonic stem (hES) cells 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 hES cell-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.