V. FUS mutations
The treatment of the subpopulation of patients with FUS -ALS is currently based on autophagy induction and alleviation of oxidative stress. Torkinib (XXXIX ) inhibition of mTOR induces autophagy more potently than rapamycin and reduces TDP-43P525Laggregates in engineered iPSC-derived spinal neurons induced by arsenite. Torkinib, improved dose-dependently the motor neuron dysfunction in three FUS Drosophila models (FUSwt, FUSR521C, FUSP525L) measured with the climbing assay (Marrone et al., 2019). Mutant FUS-aggregates are localized in stress granules and stimulating autophagy with rapamycin decreases FUS in these granules (Ryu et al., 2014). Furthermore, mutant FUS is implicated in the first stages of autophagosome formation and Rab1 overexpression restores autophagy function (Soo et al., 2015). In a controlled ongoing clinical trial (NCT03707795), betamethasone is used in ALS patients withFUS mutations to alleviate oxidative stress and improve symptoms.