Ca2+, Astrocyte Activation and Calcineurin/NFAT Signaling in Age-Related Neurodegenerative Diseases

Sompol, Pradoldej; Norris, Christopher M.

doi:10.3389/fnagi.2018.00199

Cited by 63 publications

(62 citation statements)

References 192 publications

(292 reference statements)

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“…This can occur through direct shuffling of activated down‐stream transcription factors to the nucleus after phosphorylation, dephosphorylation, or release from inhibitors. Signal transducer and activator of transcription 3 (STAT3), nuclear factor κB (NF‐κB), and nuclear factor of activated T‐cells (NFAT), the downstream effectors of the Janus kinase (JAK)‐STAT3, NF‐κB, and calcineurin‐NFAT pathways respectively, are regulated by such a mechanism (Ceyzériat, Abjean, Carrillo‐de Sauvage, Ben Haim, & Escartin, ; Sompol & Norris, ; Zhang, Lenardo, & Baltimore, ). Many signaling cascades are associated with astrocyte reaction (Ben Haim, Carrillo‐de Sauvage, Ceyzeriat, & Escartin, ; Buffo et al, ; Kang & Hebert, ), but the STAT3 pathway seems to play a prominent role in different disease conditions, acting as a master regulator of reactive astrocytes [(Ben Haim, Ceyzeriat, et al, ; Ceyzériat et al, ; Herrmann et al, ), Figure.…”

Section: What Are the Molecular Cascades Triggered In Reactive Astrocmentioning

confidence: 99%

Questions and (some) answers on reactive astrocytes

Escartin

Guillemaud

Sauvage

2019

Glia

219

180

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Astrocytes are key cellular partners for neurons in the central nervous system. Astrocytes react to virtually all types of pathological alterations in brain homeostasis by significant morphological and molecular changes. This response was classically viewed as stereotypical and is called astrogliosis or astrocyte reactivity. It was long considered as a nonspecific, secondary reaction to pathological conditions, offering no clues on disease‐causing mechanisms and with little therapeutic value. However, many studies over the last 30 years have underlined the crucial and active roles played by astrocytes in physiology, ranging from metabolic support, synapse maturation, and pruning to fine regulation of synaptic transmission. This prompted researchers to explore how these new astrocyte functions were changed in disease, and they reported alterations in many of them (sometimes beneficial, mostly deleterious). More recently, cell‐specific transcriptomics revealed that astrocytes undergo massive changes in gene expression when they become reactive. This observation further stressed that reactive astrocytes may be very different from normal, nonreactive astrocytes and could influence disease outcomes. To make the picture even more complex, both normal and reactive astrocytes were shown to be molecularly and functionally heterogeneous. Very little is known about the specific roles that each subtype of reactive astrocytes may play in different disease contexts. In this review, we have interrogated researchers in the field to identify and discuss points of consensus and controversies about reactive astrocytes, starting with their very name. We then present the emerging knowledge on these cells and future challenges in this field.

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Section: What Are the Molecular Cascades Triggered In Reactive Astrocmentioning

confidence: 99%

Questions and (some) answers on reactive astrocytes

Escartin

Guillemaud

Sauvage

2019

Glia

219

180

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“…Due to the complexity of the Ca 2+ balancing mechanisms, any malfunction in the regulatory checkpoints may contribute to the overall pathological alterations in neurodegenerative diseases. The Ca 2+ /calmodulin-dependent protein phosphatase, calcineurin has been suggested to provide a l link between Ca 2+ dysregulation and astrocyte activation [ 146 ]. Calcineurin is highly expressed by subsets of activated astrocytes in both humans and animal models, resulting in the consecutive NFAT activation and contributing to the AD neuropathology [ 147 ].…”

Section: Astrocytes In the Inflammation Associated With Neurodegeneramentioning

confidence: 99%

Astrocyte alterations in neurodegenerative pathologies and their modeling in human induced pluripotent stem cell platforms

Oksanen

Lehtonen

Jaronen

et al. 2019

Cell. Mol. Life Sci.

103

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Astrocytes are the most abundant cell type in the brain. They were long considered only as passive support for neuronal cells. However, recent data have revealed many active roles for these cells both in maintenance of the normal physiological homeostasis in the brain as well as in neurodegeneration and disease. Moreover, human astrocytes have been found to be much more complex than their rodent counterparts, and to date, astrocytes are known to actively participate in a multitude of processes such as neurotransmitter uptake and recycling, gliotransmitter release, neuroenergetics, inflammation, modulation of synaptic activity, ionic balance, maintenance of the blood–brain barrier, and many other crucial functions of the brain. This review focuses on the role of astrocytes in human neurodegenerative disease and the potential of the novel stem cell-based platforms in modeling astrocytic functions in health and in disease.

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“…Intravitreal injection of TNF may lead to activation of microglia and astrocytes in optic nerve [ 18 , 33 ]. Therefore, it is reasonable to speculate that tacrolimus suppresses the activation of glial cells and inhibits the positive feedback loop among activated glia, cytokines and CaN/NFAT [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Axonal Protection by Tacrolimus with Inhibition of NFATc1 in TNF-Induced Optic Nerve Degeneration

et al. 2019

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Tacrolimus, a calcineurin (CaN) inhibitor, has been used for treatment of refractory allergic ocular disease, although its role in optic nerve degeneration remains to be elucidated. In this study, we investigated whether tacrolimus modulates tumor necrosis factor (TNF)-mediated axonal degeneration and whether it alters nuclear factor of activated T cells (NFATc), a downstream effector of CaN signaling. Immunoblot analysis showed no significant difference in CaNAα protein levels in optic nerve on day 3, 7, or 14 after TNF injection compared with PBS injection. However, a significant increase in NFATc1 protein level was observed in optic nerve 7 days after TNF injection. This increase was negated by simultaneous administration of tacrolimus. Administration of tacrolimus alone did not change the NFATc1 protein level in comparison to that observed after PBS injection. A significant increase in TNF protein level was observed in optic nerve 14 days after TNF injection and this increase was prevented by tacrolimus. Immunohistochemical analysis showed the immunoreactivity of NFATc1 to be increased in optic nerve after TNF injection. This increased immunoreactivity was colocalized with glial fibrillary acidic protein and was suppressed by tacrolimus. Treatment of tacrolimus significantly ameliorated the TNF-mediated axonal loss. These results suggest that tacrolimus is neuroprotective against axon loss in TNF-induced optic neuropathy and that the effect arises from suppression of the CaN/NFATc1 pathway. Electronic supplementary material The online version of this article (10.1007/s11064-019-02804-6) contains supplementary material, which is available to authorized users.

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Ca2+, Astrocyte Activation and Calcineurin/NFAT Signaling in Age-Related Neurodegenerative Diseases

Cited by 63 publications

References 192 publications

Questions and (some) answers on reactive astrocytes

Questions and (some) answers on reactive astrocytes

Astrocyte alterations in neurodegenerative pathologies and their modeling in human induced pluripotent stem cell platforms

Axonal Protection by Tacrolimus with Inhibition of NFATc1 in TNF-Induced Optic Nerve Degeneration

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