MassGeneral Institute for Neurodegenerative Disease

Translating today's discoveries into tomorrow's cures

Facebook icon Twitter Icon

Disease Research Banner

Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS), or Lou Gherig’s Disease, is a life-threatening neurodegenerative disease with an estimated prevalence in the United States of 30,000 and an average life expectancy from diagnosis of only two-five years.

ALS causes the degeneration of both the upper motor neurons in the brain and the lower motor neurons in the spinal cord. This results in the progressive atrophy of associated muscle and the cells that support them, impairing the patient’s voluntary motor control ability. ALS symptoms often manifest first as muscle weakness, and then progress to difficulty speaking, swallowing, and breathing, with a majority of patients ultimately dying from respiratory failure or pneumonia.

Diagnosis of ALS can be challenging, largely being deduced by both its early symptoms, such as muscle weakness, as well as a methodical process of elimination of other diseases with symptoms that may mimic ALS such as spinal injury, vitamin deficiency, cancer, or multiple sclerosis. Autopsies on ALS patients, however, can reveal more defining abnormalities including neuronal atrophy and inclusion bodies (aggregated protein particles) in cells. ALS patients are also found to have an elevated level of the neurotransmitter, or neuron-to-neuron chemical messenger, glutamate. 

 There are both familial and apparently sporadic cases of ALS, with familial cases making up only about 10% of diagnosed cases. About 20% of these familial cases are attributable to mutations in the SOD1 enzyme, which acts to detoxify byproducts of metabolism in the mitochondria. The mutant SOD1 may comprise part of the protein aggregates seen in the cells of ALS patients. 

Mutations are also found in the gene C90RF72. In ALS patients, there can be a six nucleotide extended repeat in one of the gene’s introns potentially affecting RNA splicing. Intriguingly, this same mutation has also been linked to Frontotemporal dementia, another neurodegenerative disease. About 13 other genes have been found so far to be associated with familial ALS and many of the genes are often found mutated in sporadic ALS as well, suggesting common mechanisms. Emerging themes from the mutations identified implicate RNA processing errors and pathological protein aggregation. 

There is currently no cure for ALS. Riluzole, an NMDA receptor antagonist, is used to slow the progression of the disease. The NMDA receptor interacts with glutamate in the space between the neurons and Riluzole is thought to decrease the toxic effects of the excessive glutamate seen in ALS patients, helping to preserve the neurons. 

ALS research is focused on a better understanding of the factors involved in the disease, both genetic and environmental, in order to get a clearer picture of the mechanism, or possibly multiple mechanisms, causing the disease. Stem cells are also being used to recreate the disease in a petri dish in order to make it easier to study and to test potential drugs more quickly and safely than in humans. 

Understanding the basic biology affected by ALS pathology informs the selection of therapeutic targets. Additionally, research is focused on identifying and developing biomarkers for the disease that will allow it to be diagnosed as early as possible. Early diagnosis coupled with improved therapeutics has the potential to improve the quality and duration of ALS patient’s lives.