Novel autophagic inducers with therapeutic potential for neurodegenerative diseases
Friday, September 18, 2015 — Poster Session V
- LN Griner
- ML DePamphilis
Huntington’s disease (HD) is a neurodegenerative disorder caused by the aggregation of mutant huntingtin (mHtt) protein. Recent progress suggests that inducing autophagy can clear mHtt aggregates and protects against neurodegeneration. Here we report the discovery of a novel, highly effective, family of autophagic inducers (AI compounds) with the potential to fulfill this hypothesis. These AI compounds are structurally dissimilar to rapamycin, a well-characterized autophagic inducer. The AI compounds induce LC3-II, a key biomarker for autophagy, in a dose-dependent manner with a concomitant increase in autophagic vacuoles as shown by electron microscopy. Moreover, these events were dependent on Atg7, a gene essential for autophagy. To determine whether or not this resulted from induction of autophagy, the autophagic inhibitor Bafilomycin was included with the AI compounds. This resulted in a further accumulation of LC3-II. Furthermore, changes in LC3-II over time revealed an increase in autophagic flux. These results demonstrated that AI compounds induced autophagy. To determine their therapeutic potential, AI compounds were tested for their ability clear mHtt in an inducible HD cell model as well as in cells from HD patients. In both cases, AI compounds selectively cleared mHtt aggregates and reduced the levels of mHtt protein, while not affecting the levels of wild-type Huntingtin protein in primary cells from healthy controls. Moreover, AI compounds were effective at 10 to 100 times lower concentrations than required for rapamycin and displayed minimal cytotoxicity. These results establish a significant therapeutic potential for AI compounds in the treatment of HD and other neurodegenerative diseases.