Figure 11. A hypothetical scheme regarding the role of VHL in TDP-43 proteinopathy.

In cases of TDP-43 misfolding or unfolding such as in stress conditions, E246 would be exposed and recognized by VHL. VHL together with CUL2 would preferentially degrade fragmented forms of TDP-43 through ubiquitination. Conversely, excess amounts of VHL promote a formation of TDP-43 or mutant SOD1 inclusions at JUNQ. The loss of TDP-43 function by the misfolding or mislocalization, induce the expression of VHL.