Small molecules enhance autophagy and reduce toxicity in Huntington's disease models

The target of rapamycin (TOR) proteins regulate various cellular processes including autophagy1, which may play a protective role in certain neurodegenerative and infectious diseases2. Here we show that a primary small-molecule screen in yeast yields novel small-molecules modulators of mammalian autophagy. We first identified novel small-molecule enhancers (SMER) and inhibitors (SMIR) of the cytostatic effects of rapamycin in Saccharomyces cerevisiae. Three SMERs induced autophagy independently of rapamycin in mammalian cells, enhancing the clearance of autophagy substrates like mutant huntingtin and A53T α-synuclein, associated with Huntington’s disease (HD) and familial Parkinson’s disease, respectively3-5. These SMERs, which appear to act either independently, or downstream, of TOR, attenuated mutant huntingtin-fragment toxicity in HD cell and Drosophila models, suggesting therapeutic potential. We also screened structural analogs of these SMERs and identified additional candidate drugs enhancing autophagy. Thus, we have demonstrated proof-of-principle for a novel approach for discovery of small-molecule modulators of mammalian autophagy