Small molecules enhance autophagy and reduce toxicity in Huntington's disease models.
The target of rapamycin proteins regulate various cellular processes including autophagy, which may play a protective role in certain neurodegenerative and infectious diseases. Here we show that a primary small-molecule screen in yeast yields novel small-molecule modulators of mammalian autophagy. We first identified new 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 such as mutant huntingtin and A53T alpha-synuclein, which are associated with Huntington's disease and familial Parkinson's disease, respectively. These SMERs, which seem to act either independently or downstream of the target of rapamycin, attenuated mutant huntingtin-fragment toxicity in Huntington's disease cell and Drosophila melanogaster models, which suggests therapeutic potential. We also screened structural analogs of these SMERs and identified additional candidate drugs that enhanced autophagy substrate clearance. Thus, we have demonstrated proof of principle for a new approach for discovery of small-molecule modulators of mammalian autophagy.
Sarkar
Sovan
S
Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.
Perlstein
Ethan O
EO
Imarisio
Sara
S
Pineau
Sandra
S
Cordenier
Axelle
A
Maglathlin
Rebecca L
RL
Webster
John A
JA
Lewis
Timothy A
TA
O'Kane
Cahir J
CJ
Schreiber
Stuart L
SL
Rubinsztein
David C
DC
D000818:Animals; D001343:Autophagy / Q000187:drug effects*; D006816:Huntington Disease / Q000188:drug therapy*; D008322:Mammals; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000502:physiology*; D020123:Sirolimus / Q000037:antagonists & inhibitors
D018696:Neuroprotective Agents; D020123:Sirolimus