A small molecule p75 ^NTR ligand normalizes signalling and reduces Huntington’s disease phenotypes in R6/2 and BACHD mice

Abstract

Decreases in the ratio of neurotrophic versus neurodegenerative signalling play a critical role in Huntington’s disease (HD) pathogenesis and recent evidence suggests that the p75 neurotrophin receptor (NTR) contributes significantly to disease progression. p75 ^NTR signalling intermediates substantially overlap with those promoting neuronal survival and synapse integrity and with those affected by the mutant huntingtin (muHtt) protein. MuHtt increases p75 ^NTR -associated deleterious signalling and decreases survival signalling suggesting that p75 ^NTR could be a valuable therapeutic target. This hypothesis was investigated by examining the effects of an orally bioavailable, small molecule p75 ^NTR ligand, LM11A-31, on HD-related neuropathology in HD mouse models (R6/2, BACHD). LM11A-31 restored striatal AKT and other pro-survival signalling while inhibiting c-Jun kinase (JNK) and other degenerative signalling. Normalizing p75 ^NTR signalling with LM11A-31 was accompanied by reduced Htt aggregates and striatal cholinergic interneuron degeneration as well as extended survival in R6/2 mice. The p75 ^NTR ligand also decreased inflammation, increased striatal and hippocampal dendritic spine density, and improved motor performance and cognition in R6/2 and BACHD mice. These results support small molecule modulation of p75 ^NTR as an effective HD therapeutic strategy. LM11A-31 has successfully completed Phase I safety and pharmacokinetic clinical trials and is therefore a viable candidate for clinical studies in HD.