Repeat Expansions in C9orf72 Leads to Mislocalization of TDP-43 Outside the Nucleus and the Mishandling of RNA by TDP-43 Leads to Sporadic ALS Formation
Introduction. ALS is a progressive neurodegenerative disease whose hallmark is the gradual loss of upper and lower motor neurons and their pathways1. ALS has been reported to affect between 0.6 and 3.8 per 100,000 persons2. This disease is relentlessly progressive in most patients, with an average survival of about 3 years after symptom onset, where death is mostly attributed to respiratory failure in roughly 61% of patients1, 3. With our current knowledge on ALS, the scientific community knows not how to cure it, nor how it even comes to exist. Studies have found a link to C9orf72 caused proteinopathies on TDP-43, which leads to sporadic ALS formation4-6. Other studies have shown that a stereopure oligonucleotide that preserves C9orf72 expression reduces the pathological signatures of C9-ALS5. Methods. C9orf72 was tagged with maltose-binding protein to determine its effect on TDP-43 mislocalization and aggregation4. With a proximity ligation assay, it was determined that TDP-43 co-aggregated with the poly-GR form of C9orf724. To determine the detrimental effect that TDP-43 proteinopathies had on the integrity of the neurons, another study was performed that monitored the formation of R-loops in SH-SY5Y neuroblast-like cells, which will cause apoptosis of the cell due to double-stranded DNA breaks in the neuron6. DNA-RNA immunoprecipitation was used to determine if R-loop accumulation was present by looking for the S9.6 signal, which is a determinant of R-loop formation6. Results. The poly-GR repeat in C9orf72 led to a significant increase in TDP-43 aggregation and mislocalization in the cytoplasm compared to its poly-GA counterpart4. An increase in R-loop formation correlated with TDP-43 mislocalization6. All things considered, any alteration in the delicate balance of TDP-43 function can lead to the development of diseases like ALS. Conclusions. Studies have found that poly-GR repeats in C9orf72 can lead to sporadic ALS formation due to the formation of TDP-43 proteinopathies. With the use of stereopure oligonucleotides, these ALS symptoms can be diminished. It is important to note the importance of TDP-43 directed therapeutic research and how this is a potential avenue for future research.
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