Abnormal Intracellular Calcium Signaling and SNARE-Dependent Exocytosis Contributes to SOD1G93A Astrocyte-Mediated Toxicity in Amyotrophic Lateral Sclerosis
Abstract
Motor neurons are progressively and predominantly degenerated in ALS, which is not only induced by multiple intrinsic pathways but also significantly influenced by the neighboring glial cells. In particular, astrocytes derived from the SOD1 mutant mouse model of ALS or from human familial or sporadic ALS patient brain tissue directly induce motor neuron death in culture; however, the mechanisms of pathological astroglial secretion remain unclear. Here we investigated abnormal calcium homeostasis and altered exocytosis in SOD1G93A astrocytes. We found that purinergic stimulation induces excess calcium release from the ER stores in SOD1G93A astrocytes, which results from the abnormal ER calcium accumulation and is independent of clearance mechanisms. Furthermore, pharmacological studies suggested that store-operated calcium entry (SOCE), a calcium refilling mechanism responsive to ER calcium depletion, is enhanced in SOD1G93A astrocytes. We found that oxidant-induced increased S-glutathionylation and calcium-independent puncta formation of the ER calcium sensor STIM1 underlies the abnormal SOCE response in SOD1G93A astrocytes. Enhanced SOCE contributes to ER calcium overload in SOD1G93A astrocytes and excess calcium release from the ER during ATP stimulation. In addition, ER calcium release induces elevated ATP release from SOD1G93A astrocytes, which can be inhibited by the overexpression of dominant-negative SNARE. Selective inhibition of exocytosis in SOD1G93A astrocytes significantly prevents astrocyte-mediated toxicity to motor neurons and delays disease onset in SOD1G93A mice. Our results characterize a novel mechanism responsible for calcium dysregulation in SOD1G93A astrocytes and provide the first in vivo evidence that astrocyte exocytosis contributes to the pathogenesis of ALS.
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Increased exocytosis has been observed in SOD1-G93A astrocytes and it contributes to astrocyte-mediated toxicity.
“Interestingly, increased exocytosis has been observed in SOD1-G93A astrocytes and it contributes to the astrocyte-mediated toxicity [27].”
From Distinct repertoires of microRNAs present in mouse astrocytes compared to astrocyte-secreted exosomes (2017) · cites this paper as [27]
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- Authors
- Kawamata, H., Ng, S. K., Diaz, N., Burstein, S., Morel, L., Osgood, A., Sider, B., Higashimori, H., Haydon, P. G., Manfredi, G., & Yang, Y.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2014-02-05
- Volume
- 34
- Issue
- 6
- Pages
- 2331-2348
- ISSN
- 0270-6474
- 1529-2401
- Cited by
- 95
- References
- 7
- Language
- en
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