p75NTR: Key Functions in Neuronal Survival and Growth

The p75 neurotrophin receptor (p75NTR) plays a crucial role in the nervous system, influencing neuronal survival, apoptosis, and axonal growth. Unlike other neurotrophin receptors, its functions vary depending on cellular context, ligand availability, and co-receptor interactions. While particularly significant during development, p75NTR also affects neural plasticity and response to injury in adulthood.

Receptor Architecture

The structural organization of p75NTR determines its diverse cellular effects. As a member of the tumor necrosis factor receptor superfamily, it is a single-pass transmembrane protein with an extracellular domain, a transmembrane region, and an intracellular death domain. The extracellular domain contains four cysteine-rich repeats that facilitate binding to neurotrophins such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3). Unlike the tropomyosin receptor kinase (Trk) family, which selectively binds neurotrophins, p75NTR binds all neurotrophins with similar affinity, allowing it to regulate multiple signaling pathways.

The transmembrane domain contributes to receptor dimerization, influencing downstream signaling. While p75NTR can function as a homodimer, it often forms heterodimeric complexes with co-receptors like sortilin or Trk receptors, altering its signaling properties. These different configurations can lead to either pro-survival or pro-apoptotic outcomes depending on the cellular environment.

The intracellular death domain serves as a docking site for adaptor proteins that regulate the receptor’s signaling output. Proteins such as neurotrophin receptor-interacting factor (NRIF) and tumor necrosis factor receptor-associated factors (TRAFs) bind to this domain, influencing pathways involved in survival, cytoskeletal dynamics, and inflammatory responses. Because p75NTR lacks intrinsic kinase activity, its function is entirely dependent on these protein interactions.

Signaling Pathways

The signaling mechanisms of p75NTR depend on ligand binding, co-receptor interactions, and intracellular adaptor proteins. Unlike receptor tyrosine kinases, which directly phosphorylate signaling molecules, p75NTR relies on protein-protein interactions to propagate signals, leading to outcomes such as cell survival, apoptosis, and cytoskeletal remodeling.

One key pathway activated by p75NTR is nuclear factor kappa B (NF-κB), which promotes cell survival and inflammatory responses. Neurotrophin binding recruits TRAFs, facilitating NF-κB signaling and the expression of genes that enhance neuronal resilience. However, NF-κB activation through p75NTR is often weaker than that of other receptors, suggesting a more modulatory role in survival.

Conversely, p75NTR can also trigger apoptosis via c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) pathways. This occurs when p75NTR interacts with NRIF and other adaptor proteins that promote pro-apoptotic gene expression. Under conditions of low neurotrophin availability or when p75NTR is not engaged with Trk receptors, apoptotic signaling can dominate, leading to programmed cell death.

Another major pathway influenced by p75NTR is RhoA signaling, which regulates cytoskeletal dynamics. Activation of RhoA leads to growth cone collapse and inhibition of neurite outgrowth, affecting nerve regeneration and injury responses. The receptor’s interaction with Rho GDP dissociation inhibitor (RhoGDI) modulates RhoA activity, making p75NTR a key regulator of neuronal morphology. In some contexts, RhoA activation contributes to axonal pruning, while in others, it may hinder regeneration.

Interactions With Other Neurotrophin Receptors

p75NTR’s functional diversity stems from its ability to form receptor complexes with neurotrophin receptors, particularly Trk receptors and sortilin. These interactions refine its signaling properties, determining whether a neuron undergoes survival, apoptosis, or structural remodeling.

When p75NTR associates with Trk receptors, the outcome generally promotes neuronal survival and growth. This partnership enhances the affinity of Trk receptors for specific neurotrophins, stabilizing Trk activation and amplifying downstream signaling through pathways like phosphoinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK). This cooperative interaction is especially important during development when neurons require neurotrophic support to refine synaptic connections.

In contrast, when p75NTR forms a complex with sortilin, it shifts toward apoptotic signaling. Sortilin facilitates the binding of pro-neurotrophins, such as proNGF and proBDNF, which preferentially activate p75NTR-mediated cell death pathways. This mechanism is critical for neuronal pruning during development and is implicated in neurodegenerative conditions where excessive activation of p75NTR-sortilin complexes leads to neuronal loss.

Role in Neuronal Survival

p75NTR’s influence on neuronal survival depends on cellular context, ligand availability, and intracellular interactions. Unlike other neurotrophin receptors that consistently promote survival, p75NTR can either support neuronal viability or contribute to programmed cell death.

One way p75NTR promotes survival is by stabilizing neurotrophin interactions with Trk receptors, extending trophic support in conditions where neurotrophin availability fluctuates. This effect is particularly relevant in response to injury or metabolic stress. Activation of NF-κB through p75NTR can enhance the expression of survival-promoting genes, helping neurons endure adverse conditions.

However, when neurotrophin levels are low, p75NTR shifts toward apoptotic signaling, activating JNK and p38 MAPK pathways to eliminate excess or damaged neurons. This balance ensures that only functionally viable cells persist, illustrating p75NTR’s role as a regulatory switch rather than a direct survival mediator.

Role in Axonal Outgrowth

Beyond its role in survival, p75NTR significantly influences axonal growth and guidance during development and in response to injury. Axonal outgrowth depends on cytoskeletal rearrangement, receptor-ligand interactions, and extracellular cues, all of which p75NTR helps regulate.

A primary mechanism by which p75NTR affects axonal behavior is through RhoA signaling, which controls cytoskeletal dynamics. Activation of RhoA leads to growth cone collapse and axonal retraction, crucial for developmental pruning but potentially detrimental in regeneration. However, p75NTR can also facilitate axonal extension by modulating RhoA activity through interactions with RhoGDI, demonstrating its dual role in axonal remodeling.

p75NTR also affects neuronal responses to myelin-associated inhibitors, which limit regeneration in the injured adult nervous system. By interacting with Nogo receptors, p75NTR reinforces signaling pathways that suppress neurite extension, contributing to the central nervous system’s limited regenerative capacity. Blocking p75NTR in injury models has been shown to enhance axonal regrowth, suggesting potential therapeutic strategies for neurorepair.

Links to Neurological Disorders

Dysregulation of p75NTR is implicated in various neurological disorders, as its ability to mediate both protective and degenerative processes affects neuronal health.

In Alzheimer’s disease, elevated p75NTR levels are linked to increased neuronal apoptosis and synaptic dysfunction. Amyloid-beta, a hallmark pathological protein, interacts with p75NTR to activate pro-apoptotic signaling cascades, contributing to neuronal loss. Additionally, p75NTR’s role in axonal degeneration may worsen the breakdown of neural connections. Targeting p75NTR with small-molecule inhibitors has been explored as a therapeutic approach to preserving cognitive function.

Beyond neurodegeneration, p75NTR is also implicated in psychiatric conditions such as depression and schizophrenia. Altered neurotrophin signaling, including changes in p75NTR expression, has been observed in patients with mood disorders, suggesting a role in synaptic plasticity and stress response. In schizophrenia, disruptions in neurodevelopmental processes involving p75NTR may contribute to structural and functional abnormalities in the brain. Understanding how p75NTR signaling is altered in these disorders could offer new insights for potential treatments.