Lou Gehrig's disease, also called amyotrophic lateral sclerosis, or ALS, is a neurodegenerative disorder. It is characterized by a loss of motor neurons---nerve cells that control muscle movement throughout the body. Patients with ALS develop muscle weakness, uncontrolled twitches and eventual muscle atrophy. ALS is fatal because failure of muscles throughout the body leads to organ failure. Although several cases of ALS are considered to be acquired, there have been a number of genes involved in inherited forms of the disease.
Superoxide Dismutase 1
Mutations to the gene superoxide dismutase 1, also called SOD1, are linked to the development of Lou Gehrig's disease. The SOD1 protein is found in motor neurons and helps to protect against cell damage by free radicals. In Lou Gehrig's disease, a mutant form of SOD1 accumulates in the cells and leads to cellular damage and disease. The specific effect of mutant SOD1 on the development of ALS is still unknown.
In a 2005 study published in "Nature Medicine," Dr. G. Ralph investigated a genetic treatment for inherited ALS. He used a gene therapy technology to decrease the amount of mutant SOD1 protein in motor neuron cells in mice with Lou Gehrig's disease, and found that the gene therapy increased the lifespan of the mice by 80 percent. Although SOD1 therapy for ALS in humans has not been explored, gene therapy may be a viable treatment for Lou Gehrig's disease in the future.
Vascular Endothelial Growth Factor
Vascular endothelial growth factor, or VEGF, is a protein secreted by cells in the body that stimulates blood vessel reorganization and a range of other cellular behaviors. It is thought to be linked to Lou Gehrig's disease. VEGF binds to factors on the surface of the cell, and the cell responds with an appropriate cellular behavior. In Lou Gehrig's disease, severely decreased levels of VEGF signal to motor neurons. Although the mechanism by which VEGF affects ALS is not known, low levels of VEGF are thought to contribute to the pathogenesis of Lou Gehrig's disease. Mutations that decrease the levels of VEGF could be involved in inherited forms of ALS.
Increasing VEGF levels is thought to help treat Lou Gehrig's disease. In a 2010 study published in "Neurobiology of Disease," Dr. A. Barbeito found that treating mice with non-toxic levels of lead increased the amount of VEGF found in the nervous system. The lead prevented motor neuron loss and increased lifespan. Understanding how lead affects VEGF and ALS may lead to the development of new treatments for the disease.
Glutamate Receptors
Glutamate receptors are a complex of proteins found on the surface of cells, which bind to specific factors called neurotransmitters. When a neurotransmitter binds an glutamate receptor, this transmits a signal to a nerve cell for a flow of calcium into the cell. Mutations to a specific type of glutamate receptor is thought to be involved in the development of Lou Gehrig's disease.
Calcium accumulation within cells, which would occur with mutant receptors, is thought to play a role in the development of ALS. A 2010 study published in the "Journal of Neuroscience" explains that a gene called mGlur1, a type of glutamate receptor, could induce accumulation of calcium within motor neurons, leading to neurotoxicity. Further research into the specific action of mGlur1 in ALS may lead to the development of new treatments for the disease.
References
- "Nature Medicine"; Silencing Mutant SOD1 Using RNAi Protects Against Neurodegeneration and Extends Aurvival in an ALS Model; G. Scott Ralph et al.; April 2005
- "Neurobiology of Disease"; Lead Exposure Stimulates VEGF Expression in the Spinal Cord and Extends Survival in a Mouse Model of ALS; A. G. Barbeito et al.; March 2010
- "Journal of Neuroscience"; Metabotropic Glutamate Receptor 1 Mediates the Electrophysiological and Toxic Actions of the Cycad Derivative Beta-N-Methylamino-L-Alanine on Substantia Nigra Pars Compacta DAergic Neurons; M. L. Cucchiaroni et al.; April 2010
