Sean Krivitsky ‘27

Figure 1. Drosophila melanogaster was used by the Dubnau lab as a model organism to characterize TDP-43 pathology in ALS.

TAR-DNA-Binding protein (TDP-43) is an alternative splicing factor that, upon abnormal phosphorylation, can become mislocalized and aggregate in cells. This has been identified as a potential mechanism for the development of impactful neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD) and limbic-predominant age-related TDP-43 encephalopathy. Although TDP-43 protein pathology has been found to be induced upstream, properties of disease progression also suggest the involvement of a positive feedback loop in the mechanism of neurodegeneration. A potential explanation for this mechanism has been postulated and studied in Drosophila melanogaster models by Yung-Heng Chang of Dr. Joshua Dubnau’s lab in Stony Brook University’s Department of Neurobiology and Behavior. They have suggested that the expression of endogenous retroviruses (ERVs) is involved as a key component of this positive feedback mechanism, contributing to TDP-43 pathology and the propagation of neurodegenerative effects throughout the brain.

In their research, they employed immunofluorescent imaging in order to monitor neurodegeneration in their experiments. First, they tested the effect of ERV expression in both human neuroblastoma cells as well as fruit fly cells, and were able to confirm that its expression triggered TDP-43 pathology, namely the protein’s mislocalization, aggregation, and phosphorylation. They were also able to find that, although TDP-43 alone cannot sustain progression of disease, ERV expression acted as upstream drivers of TDP-43 pathology in human brain cancer cell lines and fruit fly models. This supports the idea that ERV expression alongside TDP-43 pathology is likely necessary for this feedback mechanism to occur and promote further neurodegeneration and TDP-43 pathology.

This study provides significant insights into a potential mechanism by which neurodegeneration in impactful diseases like ALS can occur. Given the fact that TDP-43 pathology is close to ubiquitous in many of these different neurodegenerative disease cases, the Dubnau lab’s research also further points to potential therapeutic approaches that can be developed to target this positive feedback loop. Additionally, not only do these findings hold significance to these neurodegenerative diseases, but they also expand researchers’ larger understanding of the cellular impact of ERV expression, given its involvement across other disorders including DNA damage and inflammatory signaling.

Works Cited

[1] Chang, Y., & Dubnau, J. (2023). Endogenous retroviruses and TDP-43 proteinopathy form a sustaining feedback driving intercellular spread of Drosophila neurodegeneration. Nature Communications, 14(1). https://doi.org/10.1038/s41467-023-36649-z

[2] Image retrieved from: https://pxhere.com/en/photo/1509985