Figure 7
From: ALS-linked FUS exerts a gain of toxic function involving aberrant p38 MAPK activation
Model for aberrant activation of p38 MAP kinase(s) by mutant and misfolded ALS-associated proteins. Available data (from this study and others10, 12, 20) support a model whereby mutant and misfolded forms of FUS (mFUS; left) and SOD1 (mSOD1; right) induce the aberrant activation of the p38 MAPK pathway. Hsp110 likely synergizes with other chaperones to ameliorate the effects of mSOD1 and mFUS, possibly upstream of ASK1 and additional unidentified factors. While mSOD1 and mFUS converge on p38 MAPK activation, perfusion of these proteins into squid axoplasm have differential effects on FAT; mFUS inhibits both anterograde (←) and retrograde (→) FAT (Figs 1 and 2) whereas mSOD1 only inhibits anterograde FAT10, 12, 20, consistent with inhibition of the beta and alpha isoforms of P38 MAPK, respectively12. In addition to FAT inhibition in squid (solid lines), mFUS- and mSOD1-induced activation p38 MAPK can manifest different phenotypes in mammalian systems (dashed lines), including but not limited to inhibition of axon outgrowth (Fig. 4) and enhanced susceptibility to cell stress12. This figure is adapted from Song et al. 20.
