p75 neurotrophin receptor–sortilin receptor complex (p75NTR–sortilin complex)

The p75 neurotrophin receptor (p75NTR)–sortilin receptor complex is a specialized heterodimeric signaling unit that mediates the pro-apoptotic effects of pro-neurotrophins, such as pro-nerve growth factor (proNGF) and pro-brain-derived neurotrophic factor (proBDNF) (Nykjaer et al., Nature, 2004). While mature neurotrophins promote cell survival through Trk receptors, their precursor forms bind this complex with high affinity to trigger programmed cell death via the JNK signaling pathway (Teng et al., J. Neurosci., 2005). Sortilin, a member of the Vps10p family, acts as a co-receptor that recognizes the pro-domain of the ligands, while p75NTR, a member of the tumor necrosis factor receptor superfamily, initiates the intracellular death cascade (UniProt P08138, Q99523). This complex is a significant therapeutic target in neurodegenerative diseases like Alzheimer's disease and amyotrophic lateral sclerosis (ALS), where its activation contributes to neuronal loss and synaptic dysfunction (Longo and Massa, Nat. Rev. Drug Discov., 2013). Pharmacological strategies include small molecule modulators like LM11A-31, which targets p75NTR to block degenerative signaling, and sortilin inhibitors like AL001, which are being evaluated for their ability to modulate protein trafficking and neuroprotection (Massa et al., J. Neurosci., 2006; Alector, 2024). Safety considerations for targeting this complex include potential impacts on normal developmental apoptosis and sortilin-dependent metabolic processes, such as lipid transport and progranulin regulation.

Other names

p75NTR-SORT1 complexpro-neurotrophin receptor complexNGFR-SORT1 complexLow-affinity nerve growth factor receptor–sortilin complexCD271-SORT1 complex

Inhibition of pro-neurotrophin-induced apoptotic signaling by blocking the interaction between p75NTR and sortilin or preventing ligand binding to the complex.