Endocytic clearance of TDP-43 and FUS; aggregation prone proteins linked to ALS pathology

We have discovered that TPD-43 and FUS, RNA-binding proteins that can localize in SGs during stress, and which are implicated in ALS pathology, undergoes a mechanism of protein turnover that is independent of autopahgy and proteasomal function. This turnover mechanism involves entry into the endocytosis pathway, where targeting to the vacuole (yeast) or lysosome (humans) subsequently occurs (Liu et al, 2017 Nature Communications, Liu et al, 2020, MCB). Furthermore, our data, and that of other labs, indicates this turnover mechanism exhibits therapeutic potential in ALS models.

Mechanistic characterization of how TDP-43 and FUS are degraded  by this mechanism, as well as identification of other substrates of this pathway are areas of current interest.