Improvement of BDNF signalling by P42 peptide in Huntington's disease.

Huntington's disease (HD) is caused by a mutation in the Huntingtin (HTT) protein. We previously reported that the 23aa peptide of HTT protein, P42, is preventing HD pathological phenotypes, such as aggregation, reduction of motor performances and neurodegeneration. A systemic treatment with P42 during the pre-symptomatic phase of the disease showed therapeutic potential in R6/2 mice. We here tested P42 effects when administered during the post-symptomatic phase. The P42 treatment alleviated deficits in motor performances, even when symptoms have already started. Because changes in the level and activity of brain-derived neurotrophic factor (BDNF) have been shown to play a central role in HD, we analysed the influence of P42 on BDNF deficit and associated phenotypes. Our data suggest that P42 is involved in the spatio-temporal control of bdnf and trkB mRNA and their protein levels. Related to this enhancement of BDNF-TrkB signalling, R6/2 mice treated with P42, exhibit reduced anxiety, better learning and memory performances, and better long-term potentiation (LTP) response. Finally we identified a direct influence of P42 peptide on neuronal plasticity and activity. These results suggest that P42 offers an efficient therapeutic potential not only by preventing aggregation of mutant HTT at early stages of the disease, but also by favouring some physiological functions of normal HTT, as P42 is naturally part of it, at the different stages of the disease. This makes P42 peptide potentially suitable not only to prevent, but also to treat HD.

Systemic delivery of P42 peptide: a new weapon to fight Huntington's disease.

BACKGROUND: In Huntington's disease (HD), the ratio between normal and mutant Huntingtin (polyQ-hHtt) is crucial in the onset and progression of the disease. As a result, addition of normal Htt was shown to improve polyQ-hHtt-induced defects. Therefore, we recently identified, within human Htt, a 23aa peptide (P42) that prevents aggregation and polyQ-hHtt-induced phenotypes in HD Drosophila model. In this report, we evaluated the therapeutic potential of P42 in a mammalian model of the disease, R6/2 mice. RESULTS: To this end, we developed an original strategy for P42 delivery, combining the properties of the cell penetrating peptide TAT from HIV with a nanostructure-based drug delivery system (Aonys® technology), to form a water-in-oil microemulsion (referred to as NP42T) allowing non-invasive per mucosal buccal/rectal administration of P42. Using MALDI Imaging Mass Spectrometry, we verified the correct targeting of NP42T into the brain, after per mucosal administration. We then evaluated the effects of NP42T in R6/2 mice. We found that P42 (and/or derivatives) are delivered into the brain and target most of the cells, including the neurons of the striatum. Buccal/rectal daily administrations of NP42T microemulsion allowed a clear improvement of behavioural HD-associated defects (foot-clasping, rotarod and body weights), and of several histological markers (aggregation, astrogliosis or ventricular areas) recorded on brain sections. CONCLUSIONS: These data demonstrate that NP42T presents an unprecedented protective effect, and highlight a new therapeutic strategy for HD, associating an efficient peptide with a powerful delivery technology.