LINC00205 regulates stress granule dynamics in ALS-mutated human motoneurons cross-talking with mutant FUS

Stress granules (SGs) are cytoplasmic membrane-less organelles that coordinate cellular stress responses. Notably, their dynamic nature enables rapid disassembly upon stress relief. In Amyotrophic Lateral Sclerosis (ALS), mutations in RNA-binding proteins like FUS impair SG dynamics, leading to persistent, solid-like aggregates. Although long noncoding RNAs (lncRNAs) are emerging as key regulators of ribonucleoprotein assemblies, their contribution to SG architecture and dysfunction remains poorly understood. We investigate LINC00205, a FUS-associated lncRNA enriched in SGs. CRISPR-mediated knockout of LINC00205 in human motoneurons (hMNs) expressing mutant FUS significantly reduces the number of FUS+ SGs per cell without affecting G3BP1+ SGs, indicating a specific role in pathological FUS recruitment to SGs. Remarkably, its absence accelerates SG disassembly in mutant FUS hMNs, restoring recovery dynamics to wild-type levels. To identify LINC00205’s molecular partners, we performed RNA pulldown followed by RNA-Seq, revealing PLCDX and ZNF841 as RNA interactors specifically recruited to aberrant SGs in the presence of mutant FUS. We also found that DHX36, an RNA helicase enriched in mutant FUS SGs, directly binds to LINC00205. Ongoing analyses aim to elucidate how LINC00205 shapes SG dynamics via its RNA–protein network. These findings reveal LINC00205 as a pivotal RNA scaffold in ALS-related SG pathology and a promising target for RNA-based therapies in this molecular landscape.