Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS), often referred to as "Lou Gehrig's disease," is a progressive neurodegenerative disease that affects nerve cells in the brain and spinal cord. It leads to the loss of muscle control, paralysis, and ultimately, death. Despite extensive research, the precise cause and mechanisms behind ALS remain largely unknown. However, significant advancements have been made in our understanding of this disease.

The Biology of ALS

In ALS, motor neurons deteriorate or die, and stop sending messages to muscles. This leads to muscle weakness, loss of movement, and difficulty speaking, swallowing, and breathing. However, the reason why these motor neurons begin to degenerate is not fully understood.

Genetic Factors

Approximately 5-10% of ALS cases are familial, meaning they occur more than once in a family lineage. In these cases, children have a 50% chance of inheriting the gene mutation from their parents. Mutations in several genes have been discovered to cause familial ALS. The most common genetic cause is a mutation in the C9ORF72 gene, followed by mutations in the SOD1, TARDBP, and FUS genes.

The majority of ALS cases are sporadic, meaning they occur without a clear familial history. While the cause of sporadic ALS is unclear, it is likely due to a combination of genetic and environmental factors.

Role of Protein Misfolding

Protein misfolding and aggregation is a common feature in ALS. In particular, the SOD1 protein in familial ALS cases and the TDP-43 protein in both familial and sporadic ALS cases are found in aggregated forms in motor neurons. These aggregates are believed to be toxic to cells, but it is still unclear how they contribute to motor neuron death.

Glutamate Excitotoxicity

Glutamate is a neurotransmitter that sends signals between nerve cells, including motor neurons. In ALS, glutamate levels are often higher in the spaces around nerve cells, leading to overstimulation and potential damage to these cells, a process known as excitotoxicity.

Neuroinflammation

Neuroinflammation is another key feature of ALS. As motor neurons deteriorate, immune cells in the brain and spinal cord, such as microglia and astrocytes, become activated. This can lead to inflammation and may further damage motor neurons.

Our understanding of ALS has greatly expanded over the past decades, uncovering a complex interplay of genetic, cellular, and molecular factors that contribute to motor neuron degeneration. However, much remains to be learned about this devastating disease. Ongoing research is crucial for developing effective therapies to slow disease progression, alleviate symptoms, and ultimately, find a cure for ALS.