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 ALS, because the incorporation of mislocalized ALS-associated mutant proteins such as FUSP525L make them persistent and contribute to motoneuron (MN) degeneration. Although the role of mutant proteins in SGs 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 cell–derived MNs, we demonstrate that the lncRNA LINC00205 interacts with FUSP525L and functions as a multivalent scaffold that promotes pathological SG formation. In particular, LINC00205 recruits specific molecules, like PLCXD3 and PIK3CA mRNAs and DHX36 protein, altering SGs molecular composition and increasing their persistence. Together, these findings open a new line of research on lncRNAs as regulators of SGs homeostasis and identify LINC00205 as a potential RNA-based therapeutic target in ALS.