FIGURE 5.

Proteasome dysfunction in ALS. The ubiquitin proteasome system is responsible for the degradation of poly-ubiquitinated protein substrates. Misfolded proteins are poly-ubiquitinated by the action of the E1, E2, and E3 ubiquitin ligases. Proteasome dysfunction has been implicated in ALS. Altered substrate delivery to the proteasome, mutant protein interaction with the proteasome, as in the case of mutant SOD1, and reduced proteasome function have all been implicated in ALS pathogenesis, ultimately leading to poly-ubiquitinated protein aggregate formation. The ALS-associated genes and their positions in the UPS are indicated in red, as are other ALS-associated defects. Interestingly, not only can mutant SOD1 interact with the 19S subunit of the proteasome, but mutant SOD1 is also a substrate for proteasome clearance. For further details please refer to the main text.