Mohamad Jabin

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 patients^{1, 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 formation^4-6. 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.

1. Masrori P, Van Damme P. Amyotrophic lateral sclerosis: a clinical review. Eur J Neurol. Oct 2020;27(10):1918-1929. doi:10.1111/ene.14393
2. Longinetti E, Fang F. Epidemiology of amyotrophic lateral sclerosis: an update of recent literature. Curr Opin Neurol. Oct 2019;32(5):771-776. doi:10.1097/WCO.0000000000000730
3. Wolf J, Safer A, Wohrle JC, et al. [Causes of death in amyotrophic lateral sclerosis : Results from the Rhineland-Palatinate ALS registry]. Nervenarzt. Aug 2017;88(8):911-918. Todesursachen bei amyotropher Lateralsklerose : Ergebnisse aus dem ALS-Register Rheinland-Pfalz. doi:10.1007/s00115-017-0293-3
4. Cook CN, Wu Y, Odeh HM, et al. C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy. Sci Transl Med. Sep 2 2020;12(559)doi:10.1126/scitranslmed.abb3774
5. Liu Y, Dodart JC, Tran H, et al. Variant-selective stereopure oligonucleotides protect against pathologies associated with C9orf72-repeat expansion in preclinical models. Nat Commun. Feb 8 2021;12(1):847. doi:10.1038/s41467-021-21112-8
6. Giannini M, Bayona-Feliu A, Sproviero D, Barroso SI, Cereda C, Aguilera A. TDP-43 mutations link Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage. PLoS Genet. Dec 2020;16(12):e1009260. doi:10.1371/journal.pgen.1009260