In the life disrupting disease known as amyotrophic lateral sclerosis (ALS), degeneration of upper and lower motor neurons eventually causes disability through the inability to control locomotion, speaking, eating and breathing. The most unfortunate parts of this disease are that the cause of ALS is not completely understood, treatments are limited with no cure, and ALS tends to progressively worsen over time even with treatment and therapy.
According to the ALS association, approximately 6,000 people in the U.S. are newly diagnosed with ALS each year. The average length of survival after diagnosis is three years, but there is much variability in length of survival as 5% of those diagnosed with ALS will live 20 years or more, like the famous physicist, Steven Hawking. Since ALS is such a debilitating disease, understanding of mechanisms of ALS and coming up with novel treatments will be essential to making a difference in the lives of those diagnosed with ALS.
This week we focused our learning on the paper: Oxidative stress and mitochondrial damage in the pathogenesis of ALS. This review identified 4 important possible contributors to ALS:
- Oxidative stress: occurs when a cell is unable to detoxify reactive intermediates, resulting in cellular damage. ALS tissues were found to have an accumulation of oxidative damage to proteins, lipids and DNA. This could be caused by a mutation in the SOD1 gene (superoxide dismutase), which normally acts as an antioxidant enzyme.
- Mitochondrial damage: oxidative stress can cause mitochondrial damage, creating energy deficits, calcium mishandling, and altering of RNA metabolism. Mitochondrial damage is especially important in motor neurons, which are known to have a large number of mitochondria.
- Altered RNA metabolism: Oxidative stress also causes the aggregation of RNA binding proteins (like TDP43 and FUS) into stress granules, which disrupt RNA metabolism. When RNA metabolism is disrupted, the overall health of the cell is compromised through the loss of functional proteins. Another important fact is that stress granule accumulation is common in patients with ALS.
- Unfolded protein aggregates: improper protein folding is a common to ALS pathogenesis. Stress granules may be trapping chaperones, proteins that assist in proper protein folding, having a widespread effect on cell physiology. In this situation, the protein degradation pathway is imbalanced, leading to the accumulation of misfolded proteins in ALS tissues. Improper folding of mitochondrial proteins will also affect mitochondria function!
These four cellular malfunctions found in ALS could all be impacting each other, resulting in a vicious cycle of damage to the important cellular organelles and processes that maintain a functioning motor neuron. While more research needs to be done in order to understand the complex pathways that contribute to ALS, the seeming overlap of oxidative stress and mitochondrial damage in ALS could be a potential target for future therapies to reduce the damage caused to motor neurons during the progression of ALS.
