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

p75NTR is a driver of disease pathogenesis in neurological, metabolic, and fibrotic diseases. p75NTR is highly pleiotropic interacting with multiple ligands, co-receptors, and signaling molecules. Blockade of p75NTR binding to its ligands or intracellular partners has therapeutic potential. Tissue-specific selective targeting of p75NTR may avoid potentially adverse on-target effects. The p75 neurotrophin receptor (p75NTR) 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 p75NTR in liver repair, fibrinolysis, lung fibrosis, muscle regeneration, and metabolism. Linking these various p75NTR functions more precisely to specific mechanisms marks p75NTR as an emerging candidate for therapeutic intervention in a wide range of disorders. Indeed, small molecule inhibitors of p75NTR binding to neurotrophins have shown efficacy in models of Alzheimer’s disease (AD) and neurodegeneration. Here, we outline recent advances in understanding p75NTR pleiotropic functions in vivo, and propose an integrated view of p75NTR and its challenges and opportunities as a pharmacological target. The p75 neurotrophin receptor (p75NTR) 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 p75NTR in liver repair, fibrinolysis, lung fibrosis, muscle regeneration, and metabolism. Linking these various p75NTR functions more precisely to specific mechanisms marks p75NTR as an emerging candidate for therapeutic intervention in a wide range of disorders. Indeed, small molecule inhibitors of p75NTR binding to neurotrophins have shown efficacy in models of Alzheimer’s disease (AD) and neurodegeneration. Here, we outline recent advances in understanding p75NTR pleiotropic functions in vivo, and propose an integrated view of p75NTR and its challenges and opportunities as a pharmacological target. NTs are a family of proteins that regulate survival, development, and function of neurons. The term NT is more generally reserved for four structurally related factors: Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). neurotrophins are synthesized as precursor proteins that are proteolytically cleaved to form mature neurotrophins. ProNT cleavage can occur either intracellularly by the action of furin or proconvertase, or extracellularly by the action of plasmin, matrix metalloproteinase MMP-7, or MMP-9. p75NTR is subject to proteolytic cleavage, first by a peptidase-mediated ectodomain shedding, leaving a membrane bound C-terminal fragment (p75CTF) and liberating the ECD, and then by the γ-secretase complex that targets the p75CTF, releasing a soluble intracellular domain (p75ICD) with signaling capabilities. a 15-amino acid residue peptide (Pep5; CFFRGGFFNHNPRYC) with the binding site mapped onto a hydrophobic patch framed by helices 5 and 6. Pep5 fused with the amino (N)-terminal protein transduction domain (11 amino acids) from the human immunodeficiency virus protein TAT (TAT–Pep5) competitively inhibits the interaction between p75ICD and Rho-GDI. family of tyrosine kinases that regulates survival, differentiation, synaptic strength, and plasticity in the mammalian nervous system. NTs are common ligands of Trk receptors. Each type of NT has different binding affinity toward its corresponding Trk receptor.