Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway

Abjean, Laurene; Haim, Lucile Ben; Riquelme-Pérez, Miriam; Gipchtein, Pauline; Derbois, Céline; Palomares, Marie-Ange; Petit, Fanny; Hérard, Anne‐Sophie; Gaillard, Marie-Claude; Guillermier, Martine; Gaudin-Guérif, Mylène; Sagar, Nisrine; Dufour, Noëlle; Robil, Noémie; Kabani, Mehdi; Melki, Ronald; P, De la Grange; Bémelmans, Alexis; Bonvento, Gilles; Deleuze, Jean‐François; Hantraye, Philippe; Bonnet, Eric; Brohard, Solène; Olaso, Robert; Brouillet, Emmanuel; M, Carrillo-de Sauvage; Escartin, Carole

doi:10.1101/2021.04.29.441924

Cited by 5 publications

(1 citation statement)

References 90 publications

(132 reference statements)

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“…An important characteristic of their activation is the increased release of bioactive molecules such as inflammatory factors, ATP, and glutamate [18,19,20,21,22,23,24]. Furthermore, astrocytes contain vesicles that store and release bioactive molecules in an activity-dependent manner, a principal mechanism in the pathophysiology of neurodegenerative diseases [25,26,27,28,29,30,31]. However, the specific mechanisms by which astrocytes in NPP increase the secretion of bioactive molecules remain unclear [32], 4 complicating the identification of targets for intervention.…”

Section: Introductionmentioning

confidence: 99%

Rab8a/SNARE complex activation promotes vesicle anchoring and transport in spinal astrocytes to drive neuropathic pain

Xiao,

Wang,

et al. 2024

Biomol Biomed

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Neuropathic pain (NPP) remains a clinically challenging condition, driven by the activation of spinal astrocytes and the complex release of inflammatory mediators. This study aimed to examine the roles of Rab8a and SNARE complex proteins in activated astrocytes to uncover the underlying mechanisms of NPP. The research was conducted using a rat model with chronic constriction injury (CCI) of the sciatic nerve and primary astrocytes treated with lipopolysaccharide. Enhanced expression of Rab8a was noted specifically in spinal dorsal horn astrocytes through immunofluorescence. Electron microscopy observations showed increased vesicular transport and exocytic activity in activated astrocytes, which was corroborated by elevated levels of inflammatory cytokines such as IL-1β and TNF-α detected through quantitative PCR. Western blot analyses confirmed significant upregulation of Rab8a, VAMP2, and Syntaxin16 in these cells. Furthermore, the application of botulinum neurotoxin type A (BONT/A) reduced the levels of vesicle transport-associated proteins, inhibiting vesicular transport in activated astrocytes. These findings suggest that the Rab8a/SNARE pathway in astrocytes enhances vesicle transport and anchoring, increasing the secretion of bioactive molecules that may play a crucial role in the pathophysiology of NPP. Inhibiting this pathway with BONT/A offers a novel therapeutic target for managing NPP, highlighting its potential utility in clinical interventions.

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Section: Introductionmentioning

confidence: 99%

Rab8a/SNARE complex activation promotes vesicle anchoring and transport in spinal astrocytes to drive neuropathic pain

Xiao,

Wang,

et al. 2024

Biomol Biomed

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Glial-derived mitochondrial signals impact neuronal proteostasis and aging

Bar‐Ziv¹,

Dutta²,

Hruby³

et al. 2023

Preprint

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The nervous system plays a critical role in maintaining whole-organism homeostasis; neurons experiencing mitochondrial stress can coordinate the induction of protective cellular pathways, such as the mitochondrial unfolded protein response (UPRMT), between tissues. However, these studies largely ignored non-neuronal cells of the nervous system. Here, we found that UPRMTactivation in four, astrocyte-like glial cells in the nematode,C. elegans, can promote protein homeostasis by alleviating protein aggregation in neurons. Surprisingly, we find that glial cells utilize small clear vesicles (SCVs) to signal to neurons, which then relay the signal to the periphery using dense-core vesicles (DCVs). This work underlines the importance of glia in establishing and regulating protein homeostasis within the nervous system, which can then impact neuron-mediated effects in organismal homeostasis and longevity.TeaserGlial cells sense mitochondrial stress and signal a beneficial stress signal to promote neuronal health and longevity.

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Reactive astrocytes mediate TSPO overexpression in response to sustained CNTF exposure in the rat striatum

et al. 2023

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The 18 kDa translocator protein (TSPO) is a classical marker of neuroinflammation targeted for in vivo molecular imaging. Microglial cells were originally thought to be the only source of TSPO overexpression but astrocytes, neurons and endothelial cells can also up-regulate TSPO depending on the pathological context. This study aims to determine the cellular origin of TSPO overexpression in a simplified model of neuroinflammation and to identify the molecular pathways involved. This is essential to better interpret TSPO molecular imaging in preclinical and clinical settings. We used lentiviral vectors (LV) to overexpress the ciliary neurotrophic factor (CNTF) in the right striatum of 2-month-old Sprague Dawley rats. A LV encoding for β-Galactosidase (LV-LacZ) was used as control. One month later, TSPO expression was measured by single-photon emission computed tomography (SPECT) imaging using [125I]CLINDE. The fluorescence-activated cell sorting to radioligand-treated tissue (FACS-RTT) method was used to quantify TSPO levels in acutely sorted astrocytes, microglia, neurons and endothelial cells. A second cohort was injected with LV-CNTF and a LV encoding suppressor of cytokine signaling 3 (SOCS3), to inhibit the JAK-STAT3 pathway specifically in astrocytes. GFAP and TSPO expressions were quantified by immunofluorescence. We measured a significant increase in TSPO signal in response to CNTF by SPECT imaging. Using FACS-RTT, we observed TSPO overexpression in reactive astrocytes (+ 153 ± 62%) but also in microglia (+ 2088 ± 500%) and neurons (+ 369 ± 117%), accompanied by an increase in TSPO binding sites per cell in those three cell populations. Endothelial cells did not contribute to TSPO signal increase. Importantly, LV-SOCS3 reduced CNTF-induced astrocyte reactivity and decreased global TSPO immunoreactivity (-71% ± 30%), suggesting that TSPO overexpression is primarily mediated by reactive astrocytes. Overall, this study reveals that CNTF induces TSPO in multiple cell types in the rat striatum, through the JAK2-STAT3 pathway in astrocytes, identifying this cell type as the primary mediator of CNTF effects neuroinflammatory processes. Our results highlight the difficulty to interpret TSPO imaging in term of cellular origin without addition cellular analysis by FACS-RTT or quantitative immunostainings. Consequently, TSPO should only be used as a global marker of neuroinflammation.

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Reactive astrocytes promote proteostasis in Huntington’s disease through the JAK2-STAT3 pathway

Cited by 5 publications

References 90 publications

Rab8a/SNARE complex activation promotes vesicle anchoring and transport in spinal astrocytes to drive neuropathic pain

Rab8a/SNARE complex activation promotes vesicle anchoring and transport in spinal astrocytes to drive neuropathic pain

Glial-derived mitochondrial signals impact neuronal proteostasis and aging

Reactive astrocytes mediate TSPO overexpression in response to sustained CNTF exposure in the rat striatum

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