LINC00205 acts as a multivalent scaffold promoting FUSP525L recruitment into Amyotrophic Lateral Sclerosis stress granules

Stress granules (SG) are dynamic, membrane-less ribonucleoprotein assemblies that orchestrate cellular stress responses and rapidly disassemble upon stress relief. In Amyotrophic Lateral Sclerosis (ALS), mutations in RNA-binding proteins such as Fused in Sarcoma (FUS) impair SG dynamics, promoting the formation of aberrant and persistent granules. Although long non-coding RNAs (lncRNAs) are emerging as regulators of ribonucleoprotein organization, their mechanistic role in SG architecture and pathological remodeling remains largely unexplored. Here, we identify LINC00205 as a critical RNA regulator of pathological SG dynamics in FUS P525L -associated ALS. Using Neuroblastoma cells and human induced Pluripotent Stem Cells (hiPSC)-derived Motor Neurons (MN), we show that LINC00205 is enriched in SG upon oxidative stress and directly interacts with mutant FUS P525L . Knock-out (KO) of LINC00205 selectively reduces the formation of FUS P525L -containing SG and restores physiological SG disassembly kinetics, without affecting normal SG or FUS expression levels. Mechanistically, LINC00205 acts as a multivalent RNA scaffold, directly binding mRNAs specifically enriched in pathological SG, such as PLCXD3 and PIK3CA , as well as the RNA helicase DHX36, which is preferentially associated with FUS P525L -containing SG. We demonstrate that LINC00205 promotes their specific recruitment into pathological SG, thereby contributing to the aberrant features of these assemblies. Consistent with this mechanism, LINC00205 depletion restores PIK3CA protein levels in FUS P525L MN, suggesting increased availability of this transcript for translation. Importantly, during stress recovery, LINC00205 depletion ameliorates disease-associated MN phenotypes by reducing apoptosis and preserving neurite integrity. Together, our findings uncover an active lncRNA-driven mechanism that shapes the molecular composition of aberrant ALS-related SG and regulates their persistence, establishing lncRNAs as key organizers of RNA-protein assemblies under stress and providing a conceptual framework for modulating pathological condensates.