The Proform of Glia Cell Line-Derived Neurotrophic Factor: a Potentially Biologically Active Protein

Abstract

Growing evidences have revealed that the proforms of several neurotrophins including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT3), by binding to p75 neurotrophin receptor and sortilin, could induce neuronal apoptosis and are implicated in the pathogenesis of various neurodegenerative diseases. The glial cell line-derived neurotrophic factor (GDNF), one of the most potent useful neurotrophic factors for the treatment of Parkinson's disease (PD), is firstly synthesized as the proform (proGDNF) like other neurotrophin NGF, BDNF, and NT3. However, little is known about proGDNF expression and secretion under physiological as well as pathological states in vivo or in vitro. In this study, we investigated the expression profile and dynamic changes of proGDNF in brains of aging and PD animal models, with the interesting finding that proGDNF was a predominant form of GDNF with molecular weight of about 36 kDa by reducing and nonreducing immunoblots in adult brains and was unregulated in the aging, lipopolysaccharide (LPS), and 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) insult. We further provided direct evidence that accompanied activation of primary astrocytes as well as C6 cell line induced by LPS stimulation, proGDNF was increasingly synthesized and released as the uncleaved form in cell culture. Taken together, our results strongly suggest that proGDNF may be a biologically active protein and has specific effects on the cells close to its secreting site, and a potentially important role of proGDNF signaling in the brains, in the glia-neuronal interaction or in the pathogenesis of PD, should merit further investigation.

Potential of Müller Glia for Retina Neuroprotection

“…36 Neurotrophins are translated as large (130 kDa) propolypeptides, known as pro-forms, that undergo posttranslational proteolytic cleavage to exert their neuroprotective function. 39 Pro-forms have been shown to preferentially activate p75 NTR to mediate apoptosis, whilst activation of TrK receptors by mature forms promote survival. This is illustrated by observations with the pro-forms of NGF, BDNF and NT3, which have a high-affinity ligand for p75 NTR .…”

“…Upon binding to this receptor, these neurotrophins form a heterotrimeric complex that has a marked proapoptotic effect in opposition to their mature forms. 39 NGF, BDNF and NT3 have been shown to be secreted as pro-forms and cleaved extracellularly by proteases into the mature forms. 39,40 As part of their neuroprotective function, Müller glia produce selective neurotrophins under different conditions.…”

“…39 NGF, BDNF and NT3 have been shown to be secreted as pro-forms and cleaved extracellularly by proteases into the mature forms. 39,40 As part of their neuroprotective function, Müller glia produce selective neurotrophins under different conditions. In response to glutamate, Müller glia upregulate their secretion of BDNF, NGF, NT-3, NT-4, and GDNF, suggesting that by releasing neurotrophins, these cells play an important role in preventing glutamate toxicity.…”

Behavioral sequelae of astrocyte dysfunction: focus on animal models of schizophrenia

“…BDNF acts on neurons, supporting their survival, proliferation and differentiation. The recent findings have suggested that astrocytes produce BDNF (Girardet et al, 2013; Sun et al, 2014). Overexpressing BDNF in astrocytes, Quesseveur and colleagues examined behavioral outcomes of the altered neurons-to-astrocytes BDNF ratio.…”

Glial cell line‐derived neurotrophic factor in genetically defined fear‐induced aggression

“…Quantification of protein bands was performed by means of volume densitometry using program Scion Image (Scion Corporation, http://www.scioncorp.com). proGDNF was detected at 38 kDa (Sun et al ., ), mature GDNF dimer was detected at 28 kDa (Lin et al ., ; Euteneuer et al ., ), mature GDNF monomer was detected at 24 kDa (according to the antibody manufacturer) (Fig. ) and β‐tubulin was detected at 50 kDa.…”