The proform of glia cell line-derived neurotrophic factor: a potentially biologically active protein.
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.
Institute of Neurosciences, Fourth Military Medical University, Xi'an, 710032, People's Republic of China.
Xiao-Long
XL
Sun
Bei-Yu
BY
Chen
Li
L
Duan
Yi
Y
Xia
Zhuo-Jing
ZJ
Luo
Jing-Jie
JJ
Wang
Zhi-Ren
ZR
Rao
Liang-Wei
LW
Chen
D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D010856:Columbidae; D004195:Disease Models, Animal; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D020734:Parkinsonian Disorders / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D011498:Protein Precursors / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D011498:Protein Precursors