FIGURE 7.

Speculative model depicting the potential role of UBQLN in TDP-43 trafficking. In this model TDP-43 accumulates in the cytoplasm either due to impaired nuclear import (1), overexpression (2), or misfolding (3), possibly as a result of ALS-associated point mutations. After ubiquitylation of TDP-43 (4), cytosolic UBQLN binds (5) via the interaction of its UBA domain with ubiquitin on TDP-43. UBQLN potentially then aids in delivering accumulated TDP-43 to the proteasome (6) via its UBL domain. Alternatively, UBQLN may target TDP-43 to autophagosomes (7), where it is degraded by the lysosomal pathway (8).