The p75 protein, also known as p75 neurotrophin receptor (p75NTR), is a molecule found throughout the body. It plays diverse roles in cellular processes, influencing how cells develop, function, and respond to their environment.
What is p75?
The p75 protein is a receptor on the surface of cells, acting as a “receiver” for external signals. It is a member of the tumor necrosis factor receptor superfamily, characterized by an extracellular domain with four cysteine-rich repeats, a transmembrane domain, and an intracellular death domain. These structural elements allow it to interact with other molecules and transmit signals into the cell.
P75 binds to a group of signaling molecules called neurotrophins, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4). Both the mature forms and the immature “pro-neurotrophin” forms of these molecules can bind to p75, with pro-neurotrophins often binding with higher affinity.
How p75 Influences Cell Fate
P75’s influence on cells is diverse, sometimes promoting cell survival and growth, and at other times signaling for programmed cell death. The specific outcome depends on the context, including the type of neurotrophin bound and the presence of other co-receptors. For instance, p75 can associate with Trk receptors, which are another class of neurotrophin receptors, to enhance cell survival signals.
P75 can also promote programmed cell death, known as apoptosis, a controlled process for removing damaged or unnecessary cells. This signaling often involves interactions with co-receptors like sortilin and activation of pathways involving caspase-3 and JNK.
P75 also affects neuronal plasticity, which is the brain’s ability to adapt and change. It contributes to processes like axonal growth and degeneration, influencing how neurons extend and retract their connections. For example, p75, in complex with the Nogo receptor and Lingo-1, can restrict new axonal growth in the damaged nervous system, especially in response to inhibitory proteins found in myelin. Conversely, p75 can also promote adult neurogenesis, the formation of new neurons, and influence synaptic plasticity, which involves the strengthening or weakening of connections between neurons.
p75’s Role in Neurological Conditions and Beyond
P75’s functions are relevant in neurological conditions, where its varied roles can contribute to disease progression or recovery. In neurodegenerative diseases like Alzheimer’s disease, p75 expression is increased in hippocampal neurons, where it may contribute to neuronal death pathways. P75 is also implicated in Amyotrophic Lateral Sclerosis (ALS), a disease characterized by progressive motor neuron degeneration, with increased p75 expression observed in spinal motor neurons of ALS patients and models.
P75 also plays a role in nerve injury and repair. Following nerve damage, p75 expression can be upregulated in peripheral neurons, promoting apoptosis in damaged cells. It can also influence the migration of Schwann cells, which support nerve regeneration. In central nervous system injuries, p75 is upregulated in neural stem/progenitor cells, influencing their migration towards the injury site and affecting neuronal differentiation.
Beyond the nervous system, p75 is being investigated for its involvement in other biological processes, including scar formation, energy expenditure, and the hypoxic response. These broader roles suggest that p75 may contribute to various conditions affecting tissue repair, metabolism, and inflammation. Targeting p75 is an area of ongoing research for potential therapeutic interventions.