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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Authors | Makoto Urushitani, Attila Sik, Takashi Sakurai, Nobuyuki Nukina, Ryosuke Takahashi, Jean-Pierre Julien |
Journal | Nature neuroscience
(Nat Neurosci)
Vol. 9
Issue 1
Pg. 108-18
(Jan 2006)
ISSN: 1097-6256 [Print] United States |
PMID | 16369483
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Chromogranin A
- Chromogranins
- Molecular Chaperones
- Proteasome Inhibitors
- SOD1 protein, human
- Sod1 protein, mouse
- Superoxide Dismutase
- Superoxide Dismutase-1
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Topics |
- 3T3 Cells
- Amyotrophic Lateral Sclerosis
(enzymology, genetics)
- Animals
- Astrocytes
(metabolism)
- Blotting, Western
- COS Cells
- Cells, Cultured
- Chlorocebus aethiops
- Chromogranin A
- Chromogranins
(physiology)
- Fluorescent Antibody Technique
- Gliosis
(pathology)
- Humans
- Immunoprecipitation
- Interneurons
(metabolism, physiology)
- Mice
- Mice, Transgenic
- Microscopy, Immunoelectron
- Microsomes
(enzymology)
- Molecular Chaperones
(genetics)
- Motor Neurons
(metabolism, physiology)
- Mutation
(physiology)
- Plasmids
(genetics)
- Proteasome Inhibitors
- Protein Folding
- Spinal Cord
(cytology, metabolism)
- Subcellular Fractions
(physiology)
- Superoxide Dismutase
(genetics, metabolism)
- Superoxide Dismutase-1
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