Fig. 7

Schematic representation of the effects of cleavable or C6R mHTT on autophagy. mHTT is subject to proteolysis by different proteases, with a number of cleavage sites clustering in the PEST2 domain [17]. Cleavage at D552 and D586 liberate a small fragment that is myristoylated at G553 [34] and induces autophagosome formation. However, both the N-terminal and C-terminal fragments resulting from mHTT double cleavage are toxic and interfere with autophagic cargo loading and autophagosome transport and fusion [18, 36, 43, 63]. In the C6R mice, cleavage at D586 is prevented, and we observed enhanced autophagy as well as improved degradation of C6R mHTT. In both YAC128 and C6R mice, autophagic flux and mHTT degradation can be enhanced in peripheral tissues by fasting and in the CNS by scheduled feeding