The autophagy inducer SMER28 attenuates microtubule dynamics mediating neuroprotection.

SMER28 originated from a screen for small molecules that act as modulators of autophagy. SMER28 enhanced the clearance of autophagic substrates such as mutant huntingtin, which was additive to rapamycin-induced autophagy. Thus, SMER28 was established as a positive regulator of autophagy acting independently of the mTOR pathway, increasing autophagosome biosynthesis and attenuating mutant huntingtin-fragment toxicity in cellular- and fruit fly disease models, suggesting therapeutic potential. Despite many previous studies, molecular mechanisms mediating SMER28 activities and its direct targets have remained elusive. Here we analyzed the effects of SMER28 on cells and found that aside from autophagy induction, it significantly stabilizes microtubules and decelerates microtubule dynamics. Moreover, we report that SMER28 displays neurotrophic and neuroprotective effects at the cellular level by inducing neurite outgrowth and protecting from excitotoxin-induced axon degeneration. Finally, we compare the effects of SMER28 with other autophagy-inducing or microtubule-stabilizing drugs: whereas SMER28 and rapamycin both induce autophagy, the latter does not stabilize microtubules, and whereas both SMER28 and epothilone B stabilize microtubules, epothilone B does not stimulate autophagy. Thus, the effect of SMER28 on cells in general and neurons in particular is based on its unique spectrum of bioactivities distinct from other known microtubule-stabilizing or autophagy-inducing drugs.