Extracellular poly(ADP-ribose) is a neurotrophic signal that upregulates glial cell line-derived neurotrophic factor (GDNF) levels in vitro and in vivo
| Autor: | Yasu-Taka Azuma, Hidemitsu Nakajima, Keishi Sato, Masanori Itakura, Tadayoshi Takeuchi, Sunao Nakamura |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Programmed cell death Poly Adenosine Diphosphate Ribose Biophysics In Vitro Techniques Biochemistry Neuroprotection 03 medical and health sciences Neurotrophic factors Cell Line Tumor Glial cell line-derived neurotrophic factor Extracellular Animals Viability assay Glial Cell Line-Derived Neurotrophic Factor Nerve Growth Factors Rats Wistar Molecular Biology Cells Cultured biology Parkinson Disease Cell Biology Cell biology Rats Up-Regulation Disease Models Animal 030104 developmental biology nervous system Astrocytes biology.protein Extracellular Space GDNF family of ligands Neurotrophin |
| Zdroj: | Biochemical and biophysical research communications. 484(2) |
| ISSN: | 1090-2104 |
| Popis: | Synthesis of poly(ADP-ribose) (PAR) is catalyzed by PAR polymerase-1 (PARP-1) in neurons. PARP1 plays a role in various types of brain damage in neurodegenerative disorders. In neurons, overactivation of PARP-1 during oxidative stress induces robust PAR formation, which depletes nicotinamide adenine dinucleotide levels and leads to cell death. However, the role of the newly-formed PAR in neurodegenerative disorders remains elusive. We hypothesized that the effects of PAR could occur in the extracellular space after it is leaked from damaged neurons. Here we report that extracellular PAR (EC-PAR) functions as a neuroprotective molecule by inducing the synthesis of glial cell line-derived neurotrophic factor (GDNF) in astrocytes during neuronal cell death, both in vitro and in vivo. In primary rat astrocytes, exogenous treatment with EC-PAR produced GDNF but not other neurotrophic factors. The effect was concentration-dependent and did not affect cell viability in rat C6 astrocytoma cells. Topical injection of EC-PAR into rat striatum upregulated GDNF levels in activated astrocytes and improved pathogenic rotation behavior in a unilateral 6-hydroxydopamine model of Parkinson disease in rats. These findings indicate that EC-PAR acts as a neurotrophic enhancer by upregulating GDNF levels. This effect protects the remaining neurons following oxidative stress-induced brain damage, such as that seen with Parkinson disease. |
| Databáze: | OpenAIRE |
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