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.