This is an addendum to the an earlier article by Dr. Rubinsztein and colleagues: In the addendum he includes information about inducing autophagy as a means to treat tuberculosis as well as Huntington's Disease.
Lighthouse readers are aware of the similarities between HD and other neurodegenerative disorders such that treatments may overlap. In recent years, some cancer drugs have started to look promising for Huntington's Disease as well. The report that inducing autophagy might treat HD and viral and bacterial diseases like tuberculosis, strep, and herpes means that the potential pool for funding is getting even larger.
-- Marsha L. Miller, Ph.D.
Small Molecule Enhancers of Rapamycin-Induced TOR Inhibition Promote Autophagy, Reduce Toxicity in Huntington's Disease Models and Enhance Killing of Mycobacteria by Macrophages
R. Andres Floto, Sovan Sarkar, Ethan O. Perlstein, Beate Kampmann, Stuart L. Schreiber and David C. Rubinsztein
Upregulation of autophagy may have therapeutic benefit in a range of diseases that includes neurodegenerative conditions caused by intracytosolic aggregate-prone proteins, such as Huntington's disease, and certain infectious diseases, such as tuberculosis. The best-characterized drug that enhances autophagy is rapamycin, an inhibitor of the TOR (target of rapamycin) proteins, which are widely conserved from yeast to man. Unfortunately, the side effects of rapamycin, especially immunosuppression, preclude its use in treating certain diseases including tuberculosis, which accounts for approximately 2 million deaths worldwide each year, spurring interest in finding novel drugs that selectively enhance autophagy. We have recently reported a novel two-step screening process for the discovery of such compounds. We first identified compounds that enhance the growth-inhibitory effects of rapamycin in the budding yeast Saccharomyces cerevisiae, which we termed small molecule enhancers of rapamycin (SMERs). Next we showed that three SMERs induced autophagy independently, or downstream of mTOR, in mammalian cells, and furthermore enhanced the clearance of a mutant huntingtin fragment in Huntington's disease cell models. These SMERs also protected against mutant huntingtin fragment toxicity in Drosophila. We have subsequently tested two of the SMERs in models of tuberculosis and both enhance the killing of mycobacteria by primary human macrophages.
Source: Autophagy 2007 Aug 16;3(6) [Epub ahead of print]
