A small molecule p75NTR ligand normalizes signalling and reduces Huntington's disease phenotypes in R6/2 and BACHD mice.
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.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Danielle A
DA
Simmons
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Nadia P
NP
Belichenko
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Ellen C
EC
Ford
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Sarah
S
Semaan
Behavioral and Functional Neuroscience Laboratory, Institute for Neuro-Innovation and Translational Neurosciences, School of Medicine, Stanford, California, USA.
Marie
M
Monbureau
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Sruti
S
Aiyaswamy
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Cameron M
CM
Holman
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Christina
C
Condon
Behavioral and Functional Neuroscience Laboratory, Institute for Neuro-Innovation and Translational Neurosciences, School of Medicine, Stanford, California, USA.|Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
Mehrdad
M
Shamloo
Department of Neurology and Laboratory for Computational Neurochemistry and Drug Discovery, Department of Veterans Affairs Medical Center and Department of Neurology, University of California-San Francisco, San Francisco, CA, USA.
Stephen M
SM
Massa
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.
Frank M
FM
Longo
D000818:Animals; D004195:Disease Models, Animal; D000071058:Huntingtin Protein / Q000235:genetics / Q000378:metabolism; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D007532:Isoleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009025:Morpholines / Q000494:pharmacology*; D010641:Phenotype; D011485:Protein Binding; D011897:Random Allocation; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D000071058:Huntingtin Protein; C575077:LM11A-31; D008024:Ligands; D009025:Morpholines; D017475:Receptors, Nerve Growth Factor; C517634:Ngfr protein, mouse; D007532:Isoleucine