Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis

Nat Neurosci. 2006 Jan;9(1):108-18. doi: 10.1038/nn1603. Epub 2005 Dec 20.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Amyotrophic Lateral Sclerosis / enzymology*
  • Amyotrophic Lateral Sclerosis / 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
  • Interneurons / physiology
  • Mice
  • Mice, Transgenic
  • Microscopy, Immunoelectron
  • Microsomes / enzymology
  • Molecular Chaperones / genetics
  • Motor Neurons / metabolism
  • Motor Neurons / physiology
  • Mutation / physiology*
  • Plasmids / genetics
  • Proteasome Inhibitors
  • Protein Folding
  • Spinal Cord / cytology
  • Spinal Cord / metabolism
  • Subcellular Fractions / physiology
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism*
  • Superoxide Dismutase-1


  • Chromogranin A
  • Chromogranins
  • Molecular Chaperones
  • Proteasome Inhibitors
  • SOD1 protein, human
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1