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A small molecule p75NTR 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. 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.

SUBMITTER: Simmons DA

PROVIDER: S-EPMC5418739 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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A small molecule p75NTR ligand normalizes signalling and reduces Huntington's disease phenotypes in R6/2 and BACHD mice.

Simmons Danielle A DA Belichenko Nadia P NP Ford Ellen C EC Semaan Sarah S Monbureau Marie M Aiyaswamy Sruti S Holman Cameron M CM Condon Christina C Shamloo Mehrdad M Massa Stephen M SM Longo Frank M FM

Human molecular genetics 20161101 22

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 ...[more]

PMID: 28171570

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Project description:Huntington's disease (HD) is a dominantly inherited genetic disease caused by mutant huntingtin (htt) protein with expanded polyglutamine tracts. A neuropathological hallmark of HD is the presence of neuronal inclusions of mutant htt. p62 is an important regulatory protein in selective autophagy, a process by which aggregated proteins are degraded, and it is associated with several neurodegenerative disorders including HD. Here we investigated the effect of p62 depletion in three HD model mice: R6/2, HD190QG and HD120QG mice. We found that loss of p62 in these models led to longer lifespans and reduced nuclear inclusions, although cytoplasmic inclusions increased with polyglutamine length. In mouse embryonic fibroblasts (MEFs) with or without p62, mutant htt with a nuclear localization signal (NLS) showed no difference in nuclear inclusion between the two MEF types. In the case of mutant htt without NLS, however, p62 depletion increased cytoplasmic inclusions. Furthermore, to examine the effect of impaired autophagy in HD model mice, we crossed R6/2 mice with Atg5 conditional knockout mice. These mice also showed decreased nuclear inclusions and increased cytoplasmic inclusions, similar to HD mice lacking p62. These data suggest that the genetic ablation of p62 in HD model mice enhances cytoplasmic inclusion formation by interrupting autophagic clearance of polyQ inclusions. This reduces polyQ nuclear influx and paradoxically ameliorates disease phenotypes by decreasing toxic nuclear inclusions. Gene expression profiles were analyzed to examine the effects of p62 depletion in mouse with or without mutant huntingtin exon 1 To examine the effect of p62 depletion on the transcriptome of Huntington's disease model mice, we crossed p62 knockout mice with HD model mice. We extracted total RNA from the striatum of these mice at 8 weeks and used for a microaaray analysis. The samples are HD transgenic mice with p62 knockout (HD_p62KO), HD mice with normal p62 (HD_p62WT), non-HD-transgenic mice with p62 knockout (NT_p62KO), and non-HD-transgenic mice with normal p62 (NT_p62WT).

Dataset Information

A small molecule p75NTR ligand normalizes signalling and reduces Huntington's disease phenotypes in R6/2 and BACHD mice.

Publications

A small molecule p75NTR ligand normalizes signalling and reduces Huntington's disease phenotypes in R6/2 and BACHD mice.

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