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

Stress Granules (SGs) are dynamic membrane-less organelles (MLOs) that under physiological conditions help cells respond to stress and restore homeostasis. They have recently been investigated in the context of Amyotrophic Lateral Sclerosis (ALS), because the incorporation of mislocalized ALS-associated mutant proteins like FUSP525L make them persistent and contribute to motoneuron (MN) degeneration. Although the role of mutant proteins in SG condensation is well established, the contribution of long non-coding RNAs (lncRNAs) to SG dynamics regulation remains largely unexplored. Here, using SK-N-BE cells and human induced pluripotent stem cells–derived MN, we demonstrate that the lncRNA LINC00205 interacts with FUSP525L and functions as a multivalent scaffold that promotes pathological SG formation; notably, LINC00205 knockout (KO) restores physiological SG recovery kinetics. LINC00205 recruits specific molecules, like PLCXD3 and PIK3CA mRNAs and DHX36 protein, altering SG molecular composition and increasing their persistence. Importantly, LINC00205 KO in FUSP525L MN rescues PIK3CA translation and alleviate the neuronal phenotype, reducing neurite branching defects. Together, these findings open a new line of research on lncRNAs as regulators of SG homeostasis and identify LINC00205 as a potential RNA-based therapeutic target in ALS.