Enhancement of Protein Degradation and HD Treatment

Enhancing the catabohsm of mHtt is another way to decrease its toxicity. Studies in N171-82Q transgenic mice and in the Drosophila and the zebrafish models of HD indicate that the stimulation of mHtt degradation and induction of autophagy with the mTOR inhibitor rapamycin accelerates clearance of mHtt (Williams et al., 2008). 

The activation of both processes involves mammahan target of rapamycin-dependent (e.g., by rapamycin analog CCI-779) or -independent (e.g., by lithium and calpain inhibitors) pathways. Combination treatment of these processes provides additive protection against polyQ-mediated-related neurodegeneration (Sarkar et al., 2008). 

Amiloride and benzamil have also been used to reduce the polyQ aggregation and mHtt toxicity in HD models. Benzamil increases the life span of R6/2 mice by inhibiting polyQ aggregation, reducing motor deficits, and alleviating the inhibition 

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