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Review
. 2016 Mar 17:11:24.
doi: 10.1186/s13023-016-0405-3.

The P42 peptide and Peptide-based therapies for Huntington's disease

Cecilia Marelli  1   2 , Florence Maschat  3
Affiliations
Review

The P42 peptide and Peptide-based therapies for Huntington's disease

Cecilia Marelli et al. Orphanet J Rare Dis. .

Abstract

Huntington's disease (HD) is a progressive neurodegenerative hereditary disease clinically characterised by the presence of involuntary movements, behavioural problems and cognitive decline. The disease-onset is usually between 30 and 50 years of age. HD is a rare disorder affecting approximately 1.3 in 10,000 people in the European Union. It is caused by an expanded CAG repeat in the first exon of the Huntingtin (HTT) gene, leading to an abnormal form of the Huntingtin protein (Htt) (polyQHtt), containing N-terminus, enlarged polyglutamine strands of variable length that stick together to form aggregates and nuclear inclusions in the damaged brain cells. Treatments currently used for Huntington's disease are symptomatic and aimed at temporally relieving the symptoms of the disease; although some promising therapies are on study, there is no drug capable of stopping disease progression either in the form of delaying onset or slowing disability progression. The utilization of peptides interacting with polyQ stretches or with Htt protein to prevent misfolding and aggregation of the expanded polyQ protein is a fascinating idea, because of low potential toxicity and ability to target very initial steps in the pathophysiological cascade of the disease, such as aggregation or cleavage process. Indeed, several therapeutic peptides have been developed and were found to significantly slow down the progression of symptoms in experimental models of Huntington's disease. This review is essentially focusing on the latest development concerning peptide strategy. In particular, we focused on a 23aa peptide P42, which is a part of the Htt protein. It is expected to work principally by preventing the abnormal Htt protein from sticking together, thereby preventing pathological consequences of aggregation and improving the symptoms of the disease. In the meantime, as P42 is part of the Htt protein, some therapeutic properties might be linked to the physiological actions of the peptide itself, considered as a functional domain of the Htt protein.

Keywords: Huntington’s disease; P42; Peptide-based therapy.

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Figures

Fig. 1
Fig. 1
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 [76]). 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 [55]. 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 [55]. Co-immunoprecipitation and BiFC experiments confirmed a direct interaction of P42 with N17.
Fig. 2
Fig. 2
Model of action of P42. A- In pathologic conditions, cleavage of mutant polyQHtt is increased, leading to short N-terminal fragments mostly lacking P42. N17 domains self interact, bringing together polyQHtt proteins (nucleation step). Oligomers will further form parallel ß sheets, thereby enhancing the aggregation process [64]. B- Our model is that exogenous addition of P42 allows a protective effect of polyQHtt-induced defects by directly interacting with the N17 domain of the N-terminal part of polyQHtt, therefore preventing nucleation, and consequently oligomerisation and aggregation processes.
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