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| Small molecules provide hopes for big diseases |
| Monday, 14 May 2007 | |
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Certain chemical compounds can help degrade unwanted toxic proteins within our cells by a process called autophagy. These compounds may prove useful against Huntington’s disease (HD), a neurodegenerative condition caused by a mutant protein.
In the Vedic scriptures we find that the Aryans assigned three Gods for creation, maintenance and destruction of everything in the universe. Even in the early days of civilization, wise men could understand the importance of destruction in the process of creation. It is interesting to see that systematic destruction of unwanted elements is also important to keep our body healthy. Cells degrade cytosolic proteins by two major routes. Short-lived soluble proteins are degraded by the proteasome, while longer-lived, aggregate-prone proteins and organelles in the cytosol are highly reliant on the lysosome for degradation. The major route for the delivery of aggregate-prone proteins to the lysosome is by autophagy. Prof. David Rubinsztein’s lab in University of Cambridge has showed that one can enhance the removal of toxic aggregate-prone proteins that cause diseases like Huntington's, by increasing autophagic activity. This leads to a delay of the onset of signs of this disease in fly and mouse models. A chemical compound named rapamycin is known to enhance the autophagy process, by inhibiting the mammalian 'Target Of Rapamycin' (mTOR). However, long term use of rapamycin has some side effects, and its immunosuppressive properties may lower resistance against infectious diseases. Dr. Sovan Sarkar and colleagues from Prof. David Rubinsztein’s lab, in collaboration with Prof. Stuart Schreiber’s lab at Harvard University, have systematically analyzed a library of chemical compounds and found certain compounds that enhance autophagy in mammalian cells. This results in increased removal of the mutant protein causing Huntington's Disease resulting in decreased toxicity in both cell and fruit fly models of HD. The molecules appear to act independently of rapamycin. However, combination therapy of rapamycin with any of these new compounds resulted in more effective autophagy than either alone. Furthermore, the authors also identified several structural analogs of these compounds that induced autophagy. The new chemical compounds that the authors have identified may prove very useful as therapeutic candidates for HD or related disorders like certain spinocerebellar ataxias, and specific forms of dementia caused by mutant forms of the 'tau' protein. However, a lot of work still needs to be done to translate this work into a clinical trial in patients.The compounds will need to be tested for safety in rodents and then humans, to see whether they work effectively in human brains at non-toxic concentrations. Paper in Nature Chemical Biology  |
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