Figure 2.
Unconventional secretion pathways of SOD1, TDP-43 and FUS. The cytoplasmic cargos SOD1, FUS and TDP-43, are represented by red, orange and purple circles, respectively. SOD1 is released either by a specific secretory pathway for cytoplasmic ubiquitinated misfolded proteins called MAPS65 or by an autophagic-like secretory pathway involving a specialized organelle called CUPS.71 SOD1 mutants are also secreted via exocytosis from motoneurons.72 The MAPS pathway seems also to promote wildtype TDP-43 secretion. FUS has, for instance, only been detected in extracellular vesicles from LC3+ autophagosomes.73 MAPS involves the targeting of cargos in Rab9+ (green circles) late endosomes allowing protein secretion in a vesicles-free form.65 This process depends on the binding of HSPA8 (marine blue triangle) and the deubiquitinase USP19 (brown stick) to polyubiquitinated (black circle) proteins. The CUPS-dependent pathway involves the Golgi reassembly-stacking protein (GRASP55) that appears to shuttle between the Golgi and CUPS.71