Improvement of BDNF signalling by P42 peptide in Huntington's disease
Résumé
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 spatiotemporal
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-termpotentiation
(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.