In vivo functions of p75NTR: challenges and opportunities for an emerging therapeutic target

Abstract

The p75 neurotrophin receptor (p75^NTR) functions at the molecular nexus of cell death, survival, and differentiation. In addition to its contribution to neurodegenerative diseases and nervous system injuries, recent studies have revealed unanticipated roles of p75^NTR in liver repair, fibrinolysis, lung fibrosis, muscle regeneration, and metabolism. Linking these various p75^NTR functions more precisely to specific mechanisms marks p75^NTR as an emerging candidate for therapeutic intervention in a wide range of disorders. Indeed, small molecule inhibitors of p75^NTR binding to neurotrophins have shown efficacy in models of Alzheimer's disease (AD) and neurodegeneration. Here, we outline recent advances in understanding p75^NTR pleiotropic functions in vivo, and propose an integrated view of p75^NTR and its challenges and opportunities as a pharmacological target.

Trial registration: ClinicalTrials.gov NCT03069014.

Keywords: Alzheimer’s disease; fibrinolysis; neurodegenerative diseases; neurotrophin receptors; small molecule inhibitors.

Figure 1.. p75^NTR structure and adaptor proteins involved in signaling.

p75^NTR is a single transmembrane-spanning protein with an amino-terminal ECD and a carboxy-terminal ICD. The ECD consist of 4 CRDs involved in ligand binding. The TM is involved in membrane sorting of p75^NTR. The ICD consists of the juxtamembrane adaptor protein-binding region, the DD and the C-terminal tail. p75^NTR is subject to proteolytic cleavage releasing a soluble ICD with signaling capabilities. Selected p75^NTR catalytic (red, serine-threonine kinases, protein tyrosine phosphatase, ligase and small GTPase), and non-catalytic (grey, scaffolding- and adaptor-like molecules) partners mediate diverse cellular effects, such as neurite outgrowth inhibition & HSC differentiation, cell survival, cell death, glucose uptake, cell cycle arrest, inhibition of fibrinolysis, hypoxia, lipolysis, energy expenditure, and ECM remodeling (see list of p75^NTR interactors in Table 1, reviewed by [1, 3, 6, 13]). Abbreviations: p75^NTR; p75 neurotrophin receptor, ECD; extracellular domain, TM; transmembrane domain, ICD; intracellular domain, DD; death domain, CRD; cysteine rich domain. HSC; hepatic stellate cell, ECM; extracellular matrix.

Figure 2.. Mechanism of action of p75^NTR - modulating small molecule compounds.

LM11A-31, LM11A-24, THX-B and the KGKE peptide or homologous sequence inhibit proNT binding to p75^NTR, EVT901 interacts with the p75^NTR CRD1 and inhibits p75^NTR pre-oligomerization, NSC49652 interacts with the p75^NTR TM domain and induces conformational changes and p75^NTR activity, lithium citrate prevents the association of the p75^NTR-sortilin receptor complex, s-LOTUS inhibits the interaction between NgR1 and p75^NTR, the c29 peptide inhibits p75^NTR cytoplasmic juxtamembrane death signaling, and the TAT-Pep5 peptide inhibits p75ICD and Rho-GDI interaction (see list of p75^NTR modulating small molecule compounds and peptides in Table 3). Abbreviations: p75^NTR; p75 neurotrophin receptor, ECD; extracellular domain, TM domain; transmembrane domain, ICD; intracellular domain, JTM domain; juxtamembrane domain, CRD1; cysteine rich domain 1, NgR1; Nogo receptor 1.

Figure 3.. Milestones of in vivo functions and drug targeting of p75^NTR.

Timeline of the discovery, in vivo studies in preclinical models of neurological and peripheral diseases, and the development of tools/drugs to study p75^NTR. Milestones in this timeline are cited in references [, , , , , , –, , , , , , , , , , , –148].