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Huntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine expansion near the N-terminus of huntingtin. A neuropathological hallmark of Huntington's disease is the presence of intracellular aggregates composed of mutant huntingtin N-terminal fragments in human postmortem brain, animal models, and cell culture models. It has been found that N-terminal fragments of the mutant huntingtin protein are more toxic than the full-length protein. Therefore, proteolytic processing of mutant huntingtin may play a key event in the pathogenesis of HD. Here, we present evidence that the region in huntingtin covering amino acids 116 to 125 is critical for N-terminal proteolytic processing. Within this region, we have identified mutations that either strongly reduce or enhance N-terminal cleavage. We took advantage of this effect and demonstrate that the mutation Δ121-122 within the putative cleavage region enhances N-terminal cleavage of huntingtin and the aggregation of N-terminal fragments. Furthermore, this particular deletion increased the activation of apoptotic processes and decreased neuronal cell viability. Our data indicate that the N-terminal proteolytic processing of mutant huntingtin can be modulated with an effect on aggregation and cell death rate.

Modulation of Mutant Huntingtin N-Terminal Cleavage and Its Effect on Aggregation and Cell Death