About Motor Neuron Diseases
Motor neurons are a specialized type of brain cell called neurons located within the spinal cord and the brain. They come in two main subtypes, namely the upper motor neurons and the lower motor neurons. The upper motor neurons originate in the brain and travel downward to connect with the lower motor neurons. The latter localize both in the brainstem and the spinal cord and are the mediators between the brainstem and the spinal cord and their peripheral targets, the muscles.
The activity of motor neurons is modulated by a network of other neurons, located within the spinal cord and the brain. These networks are known as motor circuits and are responsible for complex behaviors such as locomotion. Pathological perturbations in motor circuits affecting motor neurons directly or indirectly are involved in many diseases such as Amyotrophic Lateral Sclerosis and Spinal Muscular Atrophy. Research at the Motor Neuron Center is focused in unraveling and understanding the mechanisms involved in neurodegenerative diseases. Principal investigators at the MNC employ cellular and animal models using advanced genetic, molecular, morphological, and physiological tools to study the molecular, synaptic, cellular, and circuit mechanisms responsible for the cause of the disease.
Amyotrophic Lateral Sclerosis (ALS)
Amyotrophic lateral sclerosis (ALS), sometimes called Lou Gehrig's disease or classical motor neuron disease, is a rapidly progressive, invariably fatal neurological disease that attacks the nerve cells (neurons) responsible for controlling voluntary muscles. In ALS, both the upper motor neurons and the lower motor neurons degenerate or die, ceasing to send messages to muscles. Unable to function, the muscles gradually weaken, waste away, and twitch. Eventually, the ability of the brain to start and control voluntary movement is lost. Symptoms are usually first noticed in the arms and hands, legs, or swallowing muscles. Muscle weakness and atrophy occur on both sides of the body. Individuals with ALS lose their strength and the ability to move their arms and legs, and to hold the body upright. When muscles in the diaphragm and chest wall fail to function properly, individuals lose the ability to breathe without ventilatory support. The disease does not affect a person's ability to see, smell, taste, hear, or recognize touch. Although the disease does not usually impair a person's mind or personality, several recent studies suggest that some people with ALS may develop cognitive problems involving word fluency, decision-making, and memory. The cause of ALS is not known, and scientists do not yet know why ALS strikes some people and not others.
Spinal Muscular Atrophy (SMA)
Spinal Muscular Atrophy (SMA) was first described in 1891. More than a century later, in 1995, the disease-causing mutation in the Survival of Motor Neuron (SMN1) gene was discovered, and a second gene (SMN2) also was identified that helped to explain the phenotypic diversity: the more SMN2 copies, the milder the clinical phenotype. There was only a single strategic difference between the two genes, as pointed out by Umrao Monani and colleagues; and this difference introduced a splicing error in the SMN2 gene. As a result, the SMN2 gene produces full-length protein only about 10% of the time. SMA is divided phenotypically into 4 types according to clinical severity with type 1 being the most severe (and having the fewest SMN2 copies) and type 4 being the mildest. About 60% of the patients have type 1, 27% have type 2, 12% have type 3, and 1% have type 4.
SMA type 1 is truly life-threatening, and all forms of SMA are life-altering. SMA is the second most common autosomal recessive trait affecting humans, and the most common genetic cause of death in infancy. Approximately 2% of people carry this trait, and approximately 1 in every 8000 newborn babies are affected genotypically with SMA. Clinical symptoms of hypotonia, weakness, respiratory insufficiency, and scoliosis emerge at some point post-natally in these patients depending on the severity of their phenotype.
The SMN2 splicing error now can be corrected with the ISIS SMNRx therapeutic, an antisense oligonucleotide (ASO) that displaces splicing in favor of exon splice enhancement. This ASO therapeutic has been approved for clinical trials in humans, and these trials currently are being conducted at the Columbia SMA Clinical Research Center and elsewhere in the world. The SMA Clinical Research Center is affiliated with the MNC. The MNC and the SMA Clinical Research Center have been supported continuously by the SMA Foundation since their inception.