Absence of TDP-43 is difficult to digest

It is well established that TDP-43 accumulates in degenerating neurons in patients with ALS/FTLD, which might affect normal TDP-43 function. In this issue of The EMBO Journal Xia et al (2016) show a novel connection between TDP-43 loss of function and autophagy failure. Using knockdown models of TDP-43, they observed enhanced autophagosome and lysosome biogenesis through mTORC1 activity inhibition and TFEB activation. Impaired autophagosome-lysosome fusion was also observed, however in an mTORC1-independent manner. The data identify dysfunctions at multiple stages of the autophagic pathway following TDP-43 depletion that might represent possible targets of future therapeutic interventions.