Commentary: Regulating proNGF Action: Multiple Targets for Therapeutic Intervention

Abstract

Neurotrophins are initially synthesized as precursor forms, that are cleaved to release C-terminal mature forms that bind to Trk receptors to initiate survival and differentiative responses. Recent studies suggest that the precursor form of NGF (proNGF) acts as a distinct ligand by binding to a receptor complex of p75 and sortilin to initiate cell death. Induction of proNGF and p75 have been observed in multiple pathological states and injury models in the central nervous system, and blockade of proNGF/p75 interaction are efficacious in limiting neuronal apoptosis. Multiple strategies that may act to limit proNGF action are considered, as potential therapeutic targets for future development.

Diabetes-induced peroxynitrite impairs the balance of pro-nerve growth factor and nerve growth factor, and causes neurovascular injury

“…Treatment of our diabetic animals with atorvastatin exerted similar protective effects to FeTPPs in reducing peroxynitrite and 4-HNE adducts, as well restoring the balance between NGF and proNGF to normal levels. Accumulation of proNGF after injury has been detected in several diseases of the central nervous system such as Alzheimer's, where pro-oxidative and pro-inflammatory milieus can reduce protease activity and NGF cleavage [8,9]. Of note, we believe that this is the first report showing clinical and experimental evidence of significant accumulation of proNGF in the diabetic eye.…”

“…Whether retinal microglial cells play a role in the initial proNGF secretion or sustain a regulatory loop of neurotrophin production during diabetic retinopathy remains to be explored. While proNGF is cleaved intracellularly by furin, with mature NGF being trafficked to secretory vesicles [9], it is cleaved extracellulary by MMP-7 [8]. Unlike most other family members of MMPs, MMP-7 is constitutively expressed by most adult tissue and its activity is redoxregulated [30].…”

“…NGF is synthesised and secreted by glia as a precursor proform of NGF (proNGF), which is proteolytically cleaved, intracellularly by furin and extracellulary by the matrix metalloproteinase-7 (MMP-7), to generate the mature form (NGF) [8]. Under oxidative stress and inflammatory conditions, the activity of proteases is altered, possibly resulting in accumulation of proNGF in injured neuronal and vascular tissue [9]. However, little is known about the production pattern and activity of MMP-7, and the resulting imbalance between NGF and proNGF under diabetic conditions.…”

Epicatechin blocks pro-nerve growth factor (proNGF)-mediated retinal neurodegeneration via inhibition of p75 neurotrophin receptor proNGF expression in a rat model of diabetes

“…Recent findings by our group showed that diabetes-induced peroxynitrite formation impairs cleavage and maturation of NGF, leading to accumulation of its precursor 'proNGF' at the expense of the mature NGF levels, both in experimental models and in clinical diabetes [10]. Accumulation of proNGF after injury has been detected in several neurodegenerative diseases, such as Alzheimer's, [11,12]. However the role of proNGF in the diabetic retina and the specific molecular mechanism regulating proNGF production and its subsequent effects on retinal neurodegeneration are not fully understood.…”

ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation

“…ProNGF has been best characterized as a cytokine induced after neuronal injury in the central and peripheral nervous systems (Hempstead, 2009). Under these conditions, proNGF promotes neuronal apoptosis, and infusion of function-blocking antibodies specific for proNGF rescues most p75 NTR -expressing neurons after central neuron axotomy or seizures (Harrington et al, 2004;Volosin et al, 2006).…”