Inhibition of MEK5 suppresses TDP-43 toxicity via the mTOR-independent activation of the autophagy-lysosome pathway.

The most prominent hallmarks of many neurodegenerative diseases are the accumulation of misfolded protein aggregates and the death of certain neuronal populations. Autophagy is the major intracellular mechanism that degrades protein aggregates and damaged cellular components. Many studies have reported that the dysfunction of autophagy is associated with several neurodegenerative diseases, such as Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease. Here, we identified a novel mechanism of autophagy regulation. Inhibition of MEK5 reduced the level of p62 and increased the ratio of LC3-II to LC3-I, which is a marker for the activation of the autophagy-lysosome pathway (ALP). One of the most well-known regulators of the ALP is mTOR, and previous studies have reported that the major substrate of MEK5 is ERK5. However, we found that MEK5 modulates the autophagy-lysosome pathway in an mTOR- and ERK5-independent manner. Moreover, MEK5 inhibition alleviated the mislocalization of TDP-43 (an ALS-associated protein) and cell death in TDP-43-GFP-expressing neuronal cells. Taken together, these findings suggest that MEK5 is a novel autophagy modulator and that this kinase could be a therapeutic target for neurodegenerative diseases such as amyotrophic lateral sclerosis.