Extracellular poly(ADP-ribose) is a neurotrophic signal that upregulates glial cell line-derived neurotrophic factor (GDNF) levels in vitro and in vivo

Nakajima, Hidemitsu; Itakura, Masanori; Sato, K.; Nakamura, Sunao; Azuma, Yasutaka; Takeuchi, Tadayoshi

doi:10.1016/j.bbrc.2017.01.129

Cited by 7 publications

(9 citation statements)

References 26 publications

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“…Extracellular pADPr (but not mADPr) can activate toll-like receptor (TLR) signaling, which induces macrophages to secrete cytokines and promotes innate immune activation (40) ( Figure 2). In the nervous system, extracellular pADPr (but not mADPr) increased Glial-cell Derived Neurotrophic Factor (GDNF) in astrocytes (41). Consistent with the neuroprotective functions of GDNF, injection of pADPr into brain striatum mitigated disease phenotypes in a rodent model of Parkinson's disease.…”

Section: Extracellular Madpr/padpr and Signalingmentioning

confidence: 86%

“…Consistent with the neuroprotective functions of GDNF, injection of pADPr into brain striatum mitigated disease phenotypes in a rodent model of Parkinson's disease. Both studies (40,41) indicate that uptake of extracellular pADPr can regulate signaling in macrophages and neuronal cells. The origin of extracellular pADPr is unclear as PARP enzymes are largely intracellular (2), suggesting that pADPr synthesized following oxidative stress may be released into the extracellular space.…”

Section: Extracellular Madpr/padpr and Signalingmentioning

confidence: 99%

“…Extracellular pADPr activates TLR signaling, inducing macrophages to secrete cytokines (40). In the nervous system, extracellular pADPr increase Glial-cell Derived Neurotrophic Factor (GDNF) in astrocytes, playing roles in neuroprotection (41). Free cytoplasmic pADPr binds AIF triggering its release from the mitochondria into the cytoplasm, inducing parthanatos (47).…”

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confidence: 99%

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Multiple Roles for Mono- and Poly(ADP-Ribose) in Regulating Stress Responses

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2019

Trends in Genetics

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While stress-induced synthesis of mono ADP-ribose (mADPr) and poly ADP-ribose (pADPr) conjugates by PARP enzymes has been studied extensively, the removal and degradation of pADPr, and the fate of ADPr metabolites has received less attention. The observations that stressinduced pADPr undergoes rapid turnover and deficiencies in ADPr degradation phenocopy loss of pADPr synthesis suggest that ADPr degradation is fundamentally important to the cellular stress response. Recent work has identified several distinct families of pADPr hydrolyases that can degrade pADPr to release pADPr or mADPr into the cytoplasm. Further, many stress response proteins contain ADPr binding domains that can interact with these metabolites. Here, we will discuss how pADPr metabolites generated during pADPr degradation can function as signaling intermediates in processes such as inflammation, apoptosis and DNA damage responses. These studies highlight that the full cycle of ADPr metabolism, including both synthesis and degradation, is necessary for responses to genotoxic stress. Conjugation of ADP-ribose (ADPr) to proteins plays a critical signaling function in gene transcription, chromatin organization and stress responses. Poly-ADPr polymerase (PARP1) was originally thought responsible for producing all cellular ADPr (1). However, PARP1 is one of 18 human enzymes (also known as diphtheria toxin-type ADP-ribose transferases (ARTDs, See Glossary), reviewed in (2)), which can ADP ribosylate proteins. Further, families of ADPr hydrolases which cleave pADPr chains, protein-ADPr bonds or which remove the terminal mADPr from pADPr chains have been identified. In addition, multiple ADPr binding domains have been described. There are therefore both writers and erasers of ADPr as well as protein modules that can read mADPr and pADPr. Protein-mADPr, pADPr polymers (both protein-linked and soluble) and free mADPr may therefore represent distinct functional signaling effectors in the cell.

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Section: Extracellular Madpr/padpr and Signalingmentioning

confidence: 86%

Section: Extracellular Madpr/padpr and Signalingmentioning

confidence: 99%

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confidence: 99%

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Multiple Roles for Mono- and Poly(ADP-Ribose) in Regulating Stress Responses

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2019

Trends in Genetics

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“…GDNF is reported to be mainly expressed in neurons, but not in astrocytes, under normal conditions; conversely, GDNF is upregulated in astrocytes in diseased brains [23]. Nakajima et al [24] reported that astrocytes received signals from damaged neurons and produced GDNF to protect neurons against oxidative stress. In addition, it is reported that DA receptor activation, especially D1 receptor, increases GDNF expression in astrocytes [25,26].…”

Section: Release Of Neurotrophic Factorsmentioning

confidence: 99%

Neuron-Astrocyte Interactions in Parkinson’s Disease

Miyazaki

Asanuma

2020

Cells

104

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Parkinson’s disease (PD) is the second most common neurodegenerative disease. PD patients exhibit motor symptoms such as akinesia/bradykinesia, tremor, rigidity, and postural instability due to a loss of nigrostriatal dopaminergic neurons. Although the pathogenesis in sporadic PD remains unknown, there is a consensus on the involvement of non-neuronal cells in the progression of PD pathology. Astrocytes are the most numerous glial cells in the central nervous system. Normally, astrocytes protect neurons by releasing neurotrophic factors, producing antioxidants, and disposing of neuronal waste products. However, in pathological situations, astrocytes are known to produce inflammatory cytokines. In addition, various studies have reported that astrocyte dysfunction also leads to neurodegeneration in PD. In this article, we summarize the interaction of astrocytes and dopaminergic neurons, review the pathogenic role of astrocytes in PD, and discuss therapeutic strategies for the prevention of dopaminergic neurodegeneration. This review highlights neuron-astrocyte interaction as a target for the development of disease-modifying drugs for PD in the future.

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“…42 However, one study showed that extracellular PAR may function as a neuroprotective molecule by inducing the synthesis of glial cell line-derived neurotrophic factor in astrocytes both in vitro and in vivo, resulting in improved motor function in a rat model of PD. 43 Perspective PARP-1 is a signaling molecule with dual and opposite functions: cell survival, by facilitating DNA repair and maintaining genomic integrity, and cell death, via mitochondria-driven mechanisms. PARP-1 is a biomarker of disruption of cell homeostasis and oxidative stress and its excessive activation results in mitochondrial dysfunction, energy failure, and neuroinflammation.…”

Section: Involvement In Pdmentioning

confidence: 99%