A more recently described pathway called the "cyclical mTOR-independent pathway" is also able to modulate autophagy. This pathway ultimately activates calpains 1 and 2, which inhibit autophagy. Since the molecular pathway involves many molecules, there are multiple potential drug targets. Clonidine and verapamil are two drugs that have been shown to inhibit portions of this pathway, increase autophagy, and show promise as pharmaceuticals for the treatment of HD. To read more about verapamil, click here.
Calpains are a family of proteases whose cellular functions are generally poorly understood. In normal cells, calpain activity is very low, but in HD, calpains are more active. The exact mechanisms behind how calpains modulate autophagy are unknown, but it is believed that they play a role in autophagosome synthesis. The inhibition of calpains in fly and zebrafish models of HD resulted in enhanced autophagy and reduced huntingtin aggregation.
Researchers have discovered that calpains regulated autophagy in a mechanism different from mTOR. The kinase activity of mTOR was tracked by measuring the phosphorylation levels of the molecules it targets. When calpain inhibiting drugs were administered, there was no change in mTOR kinase activity even though huntingtin aggregate formation was reduced. The researchers found that calpain inhibitors could induce autophagy in cells in which mTOR is activated, further suggesting that calpains are mTOR-independent. Finally, the researchers found that mTOR inhibitors could also induce autophagy in cells in which calpains were activated.
Last Modified: 05/22/2009
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