Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis
Abstract
Here we report that chromogranins, components of neurosecretory vesicles, interact with mutant forms of superoxide dismutase (SOD1) that are linked to amyotrophic lateral sclerosis (ALS), but not with wild-type SOD1. This interaction was confirmed by yeast two-hybrid screen and by co-immunoprecipitation assays using either lysates from Neuro2a cells coexpressing chromogranins and SOD1 mutants or lysates from spinal cord of ALS mice. Confocal and immunoelectron microscopy revealed a partial colocalization of mutant SOD1 with chromogranins in spinal cord of ALS mice. Mutant SOD1 was also found in immuno-isolated trans-Golgi network and in microsome preparations, suggesting that it can be secreted. Indeed we report evidence that chromogranins may act as chaperone-like proteins to promote secretion of SOD1 mutants. From these results, and our finding that extracellular mutant SOD1 can trigger microgliosis and neuronal death, we propose a new ALS pathogenic model based on the toxicity of secreted SOD1 mutants.
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Protein aggregates released into extracellular space together with DAMPs from damaged neurons induce microglia activation and proinflammatory cytokine releasing.
“Protein aggregates released into the extracellular space together with DAMPs released from damaged neurons induce microglia activation and proinflammatory cytokines releasing.20,83,84”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [84]
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- Authors
- Urushitani, M., Sik, A., Sakurai, T., Nukina, N., Takahashi, R., & Julien, J.-P.
- Affiliations
- Centre hospitalier de l'Université Laval (CA)
- Université Laval (CA)
- RIKEN Center for Brain Science (JP)
- Corresponding author
- Julien, Jean-Pierre
- Venue
- Nature Neuroscience
- Published
- 2005-12-20
- Volume
- 9
- Issue
- 1
- Pages
- 108-118
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2034651824
- Semantic Scholar
- 6da103b1c172cd68887144303844e02b0c5552ff
- Cited by
- 419
- References
- 47
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 12 · 2023: 10 · 2022: 8 · 2021: 9 · 2020: 14 · 2019: 10 · 2018: 13 · 2017: 16 · 2016: 20 · 2015: 25 · 2014: 23 · 2013: 35 · 2012: 28
- FWCI
- 15.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion)
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- chromogranin, superoxide dismutase 1, SOD1 mutations, amyotrophic lateral sclerosis, protein secretion, neurosecretory granules, chaperone-like protein, trans-Golgi network, microglial activation, neuronal cell death, ALS pathogenesis, spinal cord
- MeSH terms
- Superoxide Dismutase-1, Amyotrophic Lateral Sclerosis, Animals, Astrocytes, Cells, Cultured, Chlorocebus aethiops, Chromogranins, Fluorescent Antibody Technique, Gliosis, Humans, Interneurons, Mice, Transgenic, Microsomes, Motor Neurons, Mutation, Plasmids, Spinal Cord, Subcellular Fractions, Superoxide Dismutase, Blotting, Western, Microscopy, Immunoelectron, 3T3 Cells, Protein Folding, Molecular Chaperones, COS Cells, Immunoprecipitation, Mice, Chromogranin A, Proteasome Inhibitors
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