A natural small molecule induces MAPT clearance via mTOR-independent autophagy.

Autophagy, the process of lysosomal degradation of biological materials within cells, is often halted abnormally in proteopathies, such as tauopathy and amyloidopathy. Thus, autophagy regulators that rescue dysregulated autophagy have great potential to treat proteopathies. We previously reported that the natural small molecule kaempferide (Kaem) induces autophagy without perturbing mTOR signaling. Here, we report that Kaem promotes lysosomal degradation of microtubule-associated protein tau (MAPT) in inducible MAPT cells. Kaem enhanced autophagy flux by mitigating microtubule-associated protein 1 light chain 3 (LC3) accumulation when MAPT expression was induced. Kaem also promoted activation of transcription factor EB (TFEB) without inhibiting mTOR and without mTOR inhibition-mediated cytotoxicity. In addition, Kaem-induced MAPT degradation was abolished in the absence of mitochondrial elongation factor Tu (TUFM), which was previously shown to be a direct binding partner of Kaem. Collectively, these results demonstrate that Kaem could be a potential therapeutic for tauopathy and reveal that TUFM can be a drug target for autophagy-driven disorders.