A small molecule p75^NTRligand 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. p75NTR signalling intermediates substantially overlap with those promoting neuronal survival and synapse integrity and with those affected by the mutant huntingtin (muHtt) protein. MuHtt increases p75NTR-associated deleterious signalling and decreases survival signalling suggesting that p75NTR could be a valuable therapeutic target. This hypothesis was investigated by examining the effects of an orally bioavailable, small molecule p75NTR 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 p75NTR 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 p75NTR 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 p75NTR 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.

Modulating Neurotrophin Receptor Signaling as a Therapeutic Strategy for Huntington’s Disease

“…The increased NF κ β signaling could be caused by mutant HTT-induced decreases in levels of inhibitor of nuclear factor κ B (I κ β α ) [ 228–230 ]. I κ β α prevents NF κ β from translocating to the nucleus to activate genes that promote inflammation and its levels are reduced in the R6/1 hippocampus [ 216 ] and R6/2 striatum [ 55 ]. Independent of its NF κ β activating effects, IKK has been shown to phosphorylate and acetylate HTT thus tagging it for clearance via autophagy and/or the ubiquitin-proteasome pathways and up-regulating IKK-related gene expression with an HDAC inhibitor decreased HTT aggregates in the cortex and/or striatum of HD mice [ 231, 232 ].…”

“…The first involves a pharmacological modulation that removes the imbalance in the ratio of p75 NTR to TrkB by lowering p75 NTR levels [ 216 ]. The second entails using small molecule ligands that selectively bind to and activate p75 NTR to increase survival signaling while reducing degenerative signaling [ 55 ].…”

“…LM11A-31 has also been examined for its effects against HD pathology in multiple mouse models of the disease. LM11A-31 restored p75 NTR -associated trophic signaling via the AKT pathway and inhibited degenerative signaling via the JNK pathway in the R6/2 and BACHD striatum [ 55 ]. It also prevented the increases in striatal RhoA/ROCK and NF- κ B signaling seen in R6/2 mice [ 55, 243 ].…”

Synaptic RTP801 Contributes to Motor Learning Dysfunction in Huntington’s Disease

“…In fact, structural alterations at the morphology and/or spine number in the striatum of the R6/1 59 and the KI 60 have been reported. This observation is also extended to other HD murine models such as N-terminal fragment R6/2 mice 61–63 and transgenic full-length htt YAC128 mice 64 . As a synaptic marker, PSD-95 levels are reduced in those HD animal models 46,65,66 , supporting our results.…”

Targeting p75 neurotrophin receptors ameliorates spinal cord injury‐induced detrusor sphincter dyssynergia in mice

“…These are small organic molecules identified as modulators of p75 NTRs through in silico screening for potential to mimic the binding activity of the loop one domain of NGF and competitively antagonize proneurotrophin binding to the p75 NTR ‐sortillin dimer . However, these molecules also have the potential to promote p75 NTR associated signaling through disinhibition and/or activation of the TrkA/B NTR ‐p75 complex. LM11A‐31 partitions mostly to the CNS and has been shown to improve motor coordination after spinal cord contusion injury in mice .…”