Many of the neurodegenerative diseases have new information coming out on it. Amyotrophic Lateral Sclerosis (ALS) is one of the diseases that people are aware due to its relation with Stephen Hawking, but are not familiar with the symptoms or cause of ALS. ALS symptoms can vary between people, but it is a gradual, painless onset of muscle weakness because it affects the motor neurons within the spinal cord. Initial symptoms can include tripping, dropping items, fatigue, and slurred speech.
Genetic mutations along with environmental factors can be seen as the cause of ALS. The cause of ALS can be sporadic (non-familial) which accounts for 90% of ALS patients or familial which accounts for 5-10% of ALS patients. A common theory is that sporadic mutation when paired with an environmental factor, can cause ALS. Of the familial ALS patients, around 60% have a genetic mutation. Most frequently heard of is the SOD1 mutation which has caught a lot of attention. However, there are other mutations that individuals should be aware of that have been linked to ALS such as FUS, TDP43, and C9orf72.
SOD1
The SOD1 mutation is responsible for 15-20% of familial cases in the world. SOD1 is an enzyme typically localized to the cytoplasm, nucleus, lysosomes, and mitochondria. It is involved in the body by attaching to copper or zinc and breaking down toxic superoxide radicals. It then forms ribonucleoprotein complexes in the brain and spinal cord. Within familial ALS, around 200 mutations in the gene have been linked. Most of the mutations result in an amino acid change within the protein of the enzyme. Mutations cause SOD1 aggregates to form in the cytoplasm and ribonucleoprotein complexes are not able to form which reduces the half-life.
FUS
The FUS mutation is responsible for around 5% of cases. The FUS protein regulates transcription by binding to DNA, prevents genetic damage by repairing DNA mistakes, and is involved in alternative splicing, processing, and transporting of mRNA to other cell structures to become a mature protein. Mutations involving this gene are found in ALS, Ewing sarcoma, and cancers (AML). Within ALS, the FUS gene can have around 85 mutations occur. The mutations usually affect building blocks in FUS protein, DNA binding, mRNA processing and transporting. This results in FUS protein and mRNA being trapped within the cell creating aggregates and stress granules. The picture below shows how the mutations can affect RNA metabolism.
TDP43
The TDP43, also referred to as TARDBP, mutation is responsible for around 5% of cases. TDP43 is a RNA-binding protein and found in very small concentrations in the cytoplasm of healthy individuals. Some of the functions of this protein are similar to the FUS protein above, including transcription and splicing of mRNA. However, TDP43 aggregates are found in the brain tissue of post-mortem ALS patients which lead to it being studied for ALS. Oxidative stress and mutations lead to more of this protein being moved into the cytoplasm and causing stress granules. There are nearly 30 mutations, the majority occurring in the C-terminal (shown in the picture below), that have been connected to ALS. The picture above shows how the mutations can affect RNA metabolism.
C9orf72
The C90orf72 mutation is responsible for 30-40% of familial cases in the US and Europe. C9orf71 is a protein found in neurons of the cerebral cortex and motor neurons of the brain and spinal cord. It is thought to play a role in the production and transportation of RNA and production of proteins. ALS occurs when a segment of the gene is largely repeated. It is not known if the repeat causes abnormal function.
ALS Mutations
