The P42 peptide. A- Location of P42 peptide within the 548 aa N-terminal part of human Huntingtin (hHtt) protein. In the schematic diagram the different domains are indicated: Polyglutamine tract (PolyQ), N17 and Proline rich (PRR) domains covering exon 1, as well as the HEAT repeats; the sites of cleavage by caspase (in red), calpain (in green) or metallomatrixprotease (MMP); posttranslational modifications, such as sumoylation (S), palmitoylation (palm), acetylation (Ac) and some of the phosphorylation (P) sites (modified from ). The amino acid sequence of P42 is shown (in blue). B- Cultured HeLa cells co-transfected with polyQ-hHtt-GFP presenting cytoplasmic aggregates (in green); co-transfection with polyQ-hHtt-GFP and P42 prevents aggregate formation . C- Possible mechanism of action of P42 is an interaction with the Htt protein at the N17 or at the Proline Reach region (PRR); interaction with the polyQ domain was excluded on the basis of lack of efficacy in other polyQ-induced disease models . Co-immunoprecipitation and BiFC experiments confirmed a direct interaction of P42 with N17.