Background
Many diseases, such as amyotrophic lateral sclerosis (ALS) have damaged, clumped together (or aggregated) proteins as a hallmark of disease.The processes in the cell that lead to the accumulation of damaged proteins and how this relates to disease are not well understood. Proteins that fulfil specific functions in the human body are being produced all the time. This process, however, does not always go as planned and can result in proteins being made incorrectly or sticking together, forming aggregates, thought to be toxic to cells. Therefore, protein quality control measures are very important to ensure the cell’s health and survival. There are two main processes that dispose of faulty and damage proteins in the body: autophagy, which degrades protein aggregates, and the ubiquitin-proteasome system (UPS), which degrades single damaged proteins.
Why is the study important?
How any defects in the autophagy and UPS protein quality control systems contribute to ALS remains poorly understood. In this study, Tadokoro et al (2021) attempt to shed a light on the relationship between defective protein quality control measures and the development of ALS.
What did the authors do and how did they do it?
The authors used specific drugs to block the two protein degradation pathways in the spinal cords of mouse models of ALS that reproduce the disease course at well-defined weeks of age. They treated the mice with drugs at 10, 14 and 18 weeks of age to map the importance of the UPS and/or autophagy dysfunction at different stages of the disease. The mice were culled, spinal cord tissue collected and the important markers of the UPS, autophagy, and proteins marked for degradation (called ubiquitin) looked for within.
What are the results?
The results of the study indicate that blocking the UPS in 18-week old ALS mice worsened the death of motor neurons compared to mice which were not treated with the UPS inhibitor. Interestingly, the support cells of the brain and spinal cord, called astrocytes, accumulated more damaged proteins than the motor neuron nerve cells themselves, which are the cell type that degenerates in ALS. The authors also observed an increase in autophagy markers in astrocytes and motor neurons, especially in 14-and 18-week old mice, which represent late stages of the disease. The authors demonstrate, however, that the presence of these makers does not translate to successful autophagy and conclude that autophagy is impaired in late-stage ALS mice regardless of whether a drug treatment was administered or not.
What do the finding mean going forward for people with the disease?
Overall, a further blockage of the UPS and/or autophagy exacerbates the symptoms of ALS in these mice, especially when the disease is in its advanced stages. This study sheds some light on the processes happening on the level of cells in the spinal cord of ALS patients, which need to be understood better in order for better drug therapies to be developed and prescribed. Indeed, mapping out how exactly the cells respond to further disruptions to their protein degradation pathways at later stages of the disease may one day help inform new drug therapies for ALS patients at early stages of the diseases that enhance these pathways.