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

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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.

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Abbreviations

BDNF:

Brain-derived neurotrophic factor

bFGF:

Basic fibroblast growth factor

DMEM-HG:

Dulbecco’s modified Eagle’s medium-high glucose

GDNF:

Glia cell line-derived neurotrophic factor

GFAP:

Glial fibrillary acidic protein

GFRα1:

GDNF family receptor α1

KA:

Kainic acid

LPS:

Lipopolysaccharide

matGDNF:

Mature glia cell line-derived neurotrophic factor

MANF:

Mesencephalic astrocyte-derived neurotrophic factor

mNTs:

Mature neurotrophins

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NGF:

Nerve growth factor

NT-3:

Neurotrophin-3

PBS:

Phosphate buffered saline

PD:

Parkinson’s disease

proBDNF:

Proform of brain-derived neurotrophic factor

proGDNF:

Proform of glia cell line-derived neurotrophic factor

proNGF:

Proform of nerve growth factor

proNTs:

Proneurotrophins

proNT3:

Proform of neurotrophin-3

p75NTR:

p75 neurotrophin receptor

Ret:

Rearranged during transformation

rhGDNF:

Recombinant human GDNF

SNc:

Substantia nigra pars compacta

SNr:

Substantia nigra pars reticularis

SorLA:

Sorting protein-related receptor with A-type repeats

TH:

Tyrosine hydroxylase

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Acknowledgments

This work was supported by grants from the National Science Basic Research Project (2011CB504103, 2012CB525002) and National Natural Science Foundation of China (81071609, 30970862, and 81272346). We authors also especially thank Professor Mart Saarma, University of Helsinki, Finland, for generously providing the anti-proGDNF antibody in this study.

Conflict of interest

The authors declare that there are no conflicts of interest.

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Authors and Affiliations

  1. Institute of Neurosciences, Fourth Military Medical University, Xi’an, 710032, People’s Republic of China

    Xiao-Long Sun, Li Duan, Yi Xia, Zhi-Ren Rao & Liang-Wei Chen

  2. Department of Neurology, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    Xiao-Long Sun & Zhi-Ren Rao

  3. Department of Orthopedics, Xijing Hospital, Fourth Military Medical University, Xi’an, 710032, China

    Bei-Yu Chen & Zhuo-Jing Luo

  4. Department of Gastroenterology, Tangdou Hospital, Fourth Military Medical University, Xi’an, 710038, China

    Jing-Jie Wang

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  1. Xiao-Long Sun
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Correspondence to Zhi-Ren Rao or Liang-Wei Chen.

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Xiao-Long Sun, Bei-Yu Chen, and Li Duan have equal contributions to this work.

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Sun, XL., Chen, BY., Duan, L. et al. The Proform of Glia Cell Line-Derived Neurotrophic Factor: a Potentially Biologically Active Protein. Mol Neurobiol 49, 234–250 (2014). https://doi.org/10.1007/s12035-013-8515-6

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