Given the more toxic nature of N-terminal huntingtin fragments and the evidence of natural generation and accumulation of N-terminal expanded huntingtin fragments in HD mouse brains (Davies et al., 1997; Hackam et al., 1998; Reddy et al., 1998; Hodgson et al., 1999; Schilling et al., 1999; Zhou et al., 2003; Li and Li, 2004; Jones and Hughes, 2011), it stands to reason that cleavage at these sites plays a role in enhancing toxicity in HD. Here, HTT is linked to Huntington disease.