Fig. 4.

Proposed schematic showing the role of six major proteins in causing ALS-reduced VEGF may be responsible for the hypoxia in brain because of which HIF-1α (hypoxia inducing factor-1α) gets activated consequently inducing ANG activation to compensate hypoxia. Because VEGF is reduced, its receptor soluble VEGFR2 may also be downregulated. Decreased VEGF may also lead to enhanced TDP-43 which may compensate for reduced VEGF by increasing its expression. Decreased OPTN also leads to disruption of NLS (nuclear localization signal) of TDP- 43 due to which it gets accumulated in the cytoplasm. ALS, amyotrophic lateral sclerosis; ANG, angiogenin; OPTN, optineurin; TDP, TAR DNA binding protein; VEGF, vascular endothelial growth factor; VEGFR2, VEGF receptor 2.