c-Jun, JNK/SAPK Kinase and Transcription Factor NF-κB Are Selectively Activated in Astrocytes, but not Motor Neurons, in Amyotrophic Lateral Sclerosis

Migheli, Antonio; Piva, Roberto; Atzori, Christiana; Troost, Dirk; Schiffer, Davide

doi:10.1097/00005072-199712000-00006

Cited by 146 publications

(94 citation statements)

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“…DNA damage to astrocytes has been reported in a variety of neuropathological conditions, including Pick's disease (Gleckman et al 1999), FTD (Su et al (Migheli et al 1997) as well as AD (Lucassen et al 1997;Petito and Roberts 1995). In these latter studies, DNA damage was found in the reactive (Parkinson's disease, FTD, ALS) or non-reactive (ALS) astrocytes and had the features of fragmentation or degeneration, which seemed to appear prior to or unrelated to apoptotic cell death.…”

Section: Discussionmentioning

confidence: 94%

Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes

Myung

Zhu

Kruman

et al. 2008

AGE

146

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Phosphorylation of the histone family is not only a response to cell signaling stimuli, but also an important indicator of DNA damage preceding apoptotic changes. While astrocytic degeneration, including DNA damage, has been reported in Alzheimer disease (AD), its pathogenetic significance is somewhat unclear.In an effort to clarify this, we investigated the expression of γH2AX as evidence of DNA damage in astrocytes to elucidate the role of these cells in the pathogenesis of AD. In response to the formation of double-stranded breaks in chromosomal DNA, serine 139 on H2AX, a 14-kDa protein that is a member of the H2A histone family and part of the nucleosome structure, becomes rapidly phosphorylated to generate γH2AX. Using immunocytochemical techniques, we found significantly increased levels of γH2AX in astrocytes in regions know to be vulnerable in AD, i.e., the hippocampal regions and cerebral cortex. These results suggest that astrocytes contain DNA damage, possibly resulting in functional disability, which in turn reduces their support for neurons. These findings further define the role of astrocyte dysfunction in the progression of AD.

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Section: Discussionmentioning

confidence: 94%

Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes

Myung

Zhu

Kruman

et al. 2008

AGE

146

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“…JNK activation was also found in spinal astrocytes after amyotrophic lateral sclerosis (Migheli et al, 1997). Furthermore, JNK activation has been shown in spinal astrocytes after partial sciatic nerve lesion, but only one time point (21 d) was examined in this study (Ma and Quirion, 2002).…”

Section: Jnk Activation In the Spinal Cord And Neuropathic Painmentioning

confidence: 90%

A Peptide c-Jun N-Terminal Kinase (JNK) Inhibitor Blocks Mechanical Allodynia after Spinal Nerve Ligation: Respective Roles of JNK Activation in Primary Sensory Neurons and Spinal Astrocytes for Neuropathic Pain Development and Maintenance

Zhuang¹,

Wen²,

Zhang³

et al. 2006

J. Neurosci.

475

500

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“…2c,d), pJNK is only expressed in a portion of spinal astrocytes (Zhuang et al, 2006a). JNK activation also occurs in spinal astrocytes 3 weeks after partial sciatic nerve injury (Ma and Quirion, 2002) and in amyotrophic lateral sclerosis (Migheli et al, 1997). JNK is also activated in spinal astrocytes in another chronic pain condition following adjuvant-induced inflammation (Zhuang and Ji, unpublished observation).…”

Section: Activation Of the Jnk Cascade In Spinal Astrocytes And Neuromentioning

confidence: 95%

Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

et al. 2006

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Although pain is regarded traditionally as neuronally mediated, recent progress shows an important role of spinal glial cells in persistent pain sensitization. Mounting evidence has implicated spinal microglia in the development of chronic pain (e.g. neuropathic pain after peripheral nerve injury). Less is known about the role of astrocytes in pain regulation. However, astrocytes have very close contact with synapses and maintain homeostasis in the extracellular environment. In this review, we provide evidence to support a role of spinal astrocytes in maintaining chronic pain. In particular, cJun N-terminal kinase (JNK) is activated persistently in spinal astrocytes in a neuropathic pain condition produced by spinal nerve ligation. This activation is required for the maintenance of neuropathic pain because spinal infusion of JNK inhibitors can reverse mechanical allodynia, a major symptom of neuropathic pain. Further study reveals that JNK is activated strongly in astrocytes by basic fibroblast growth factor (bFGF), an astroglial activator. Intrathecal infusion of bFGF also produces persistent mechanical allodynia. After peripheral nerve injury, bFGF might be produced by primary sensory neurons and spinal astrocytes because nerve injury produces robust bFGF upregulation in both cell types. Therefore, the bFGF/JNK pathway is an important signalling pathway in spinal astrocytes for chronic pain sensitization. Investigation of signaling mechanisms in spinal astrocytes will identify new molecular targets for the management of chronic pain.

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c-Jun, JNK/SAPK Kinase and Transcription Factor NF-κB Are Selectively Activated in Astrocytes, but not Motor Neurons, in Amyotrophic Lateral Sclerosis

Cited by 146 publications

References 0 publications

Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes

Evidence of DNA damage in Alzheimer disease: phosphorylation of histone H2AX in astrocytes

A Peptide c-Jun N-Terminal Kinase (JNK) Inhibitor Blocks Mechanical Allodynia after Spinal Nerve Ligation: Respective Roles of JNK Activation in Primary Sensory Neurons and Spinal Astrocytes for Neuropathic Pain Development and Maintenance

Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway

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