Modulation of RNA-dependent Interactions in Stress Granules Prevents Persistent TPD-43 accumulation in ALS/FTD
- Author(s): Fang, Mark Yang
- Advisor(s): Yeo, Gene W.
- et al.
Stress granules (SG) form during cellular stress and have been linked to neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). Strategies to modulate SGs have the potential to yield insights into their role in pathophysiology. We performed a high-content screen to identify small molecules that alter SG properties in proliferative cells and iPSC-derived motor neurons (iPS-MNs). One major class of hit compounds are nucleic acid intercalating molecules that disrupt recruitment of ALS-associated RNA-binding proteins (RBPs), such as TDP-43 and FUS/TLS, into SGs and reduce accumulation of cytoplasmic TDP-43 in iPS-MNs from ALS patients. These findings corroborate our biochemical results indicating that SGs accumulate ALS-associated RBPs in their shells in an RNA-dependent manner. Thus, SGs contribute to persistent accumulation of TDP-43, and nucleic acid intercalating compounds represent a promising new therapeutic approach for treating ALS/FTD.