Paper

Modulation of RNA-dependent interactions in stress granules prevents persistent TDP-43 accumulation in ALS/FTD

Fang, Mark Y, Markmiller, Sebastian, Bushway, Paul J, Mercola, Mark M, Yeo, Gene, Ding, Sheng, Vu, Anthony Q, Dowdle, William E, Lewcock, Joseph W

2018

Overview

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.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Amyotrophic lateral sclerosis / Dementia disorders / Frontotemporal dementia / Motor neurons / Neurodegenerative diseases / Neuroscience / Pathophysiology / Ribonucleic acid / RNA / RNA-binding protein