Mutant superoxide dismutase 1 (SOD1) has been linked to one-fifth of inherited cases of amyotrophic lateral sclerosis (ALS), where its misfolded form appears to damage motor neurons. But SOD1 does not act alone. Work presented by Jean-Pierre Julien at the André-Delambre Foundation Symposium on ALS, held 25-26 September in Québec City, builds on previous evidence for an accomplice, the chromogranins. Julien, Samer Abou Ezzi, and colleagues at Laval University in Québec City found that mice carrying mutant SOD1 and an excess of chromogranin A got sick earlier than mSOD1 animals with normal levels of chromogranins. They also found evidence for chromogranin B involvement in risk for ALS in people. The work suggests chromogranins act to exacerbate the toxicity of misfolded SOD1.

Chromogranins A and B are secretory vesicle components of unknown function in the nervous system. Julien’s group became interested in the proteins when a yeast two-hybrid screen using mSOD1 as bait pulled out chromogranin A. Both chromogranins immunoprecipitated with mutant SOD1, but not wild-type SOD1 (see ARF related news story on Urushitani et al., 2006). The chromogranins appear to require a domain similar to heat-shock protein sequences to bind mSOD1, suggesting they may recognize the mutant protein’s improper conformation. In human studies by another group, chromogranins co-localized with SOD1 in intracellular aggregates in tissue from people who had ALS (Schrott-Fischer et al., 2009). Chromogranins have also been found in Aβ plaques in Alzheimer disease (Marksteiner et al., 2000), and in prion deposits in Creutzfeld-Jakob disease (Rangon et al., 2003).

To further investigate the chromogranin-mSOD1 interaction in disease, Julien and colleagues engineered mice with the chromogranin A gene driven by the human Thy1 promoter, which is active in the nervous system. The mice express twice the normal amount of chromogranin A in neurons. They crossed these mice with animals expressing human SOD1-G37R. The double mutant mice exhibited symptoms of motor neuron disease one month earlier than their mSOD1 single-mutant parents. The double mutants had increased degeneration of motor neurons, compared to SOD1-G37R mice, as well.

However, the excess chromogranin A did not speed up the final stages of the disease; the double mutant mice survived for the same length of time as single mutants. Julien hypothesized that early on, the animal’s full complement of motor neurons produced plenty of chromogranin A and mSOD1, accelerating disease onset. But as motor neurons died, there were fewer of them to produce the damaging proteins. In later stages, then, the rate of disease slowed to normal.

How does chromogranin A accelerate motor neuron degeneration? Using an antibody specific for misfolded SOD1, the researchers found that the double mutants had more of the malformed species than did single mutant mice. Julien hypothesized that chromogranin A binds and stabilizes the misfolded protein, allowing it to hang around longer and do more damage. Alternatively, he suggested, the excess chromogranin A may promote secretion of misfolded SOD1 into the extracellular space where it is cytotoxic.

Previous results indicated that chromogranins promote secretion of mSOD1 (Urushitani et al., 2006), and aggregated mSOD1 is found in the endoplasmic reticulum and Golgi, along the secretory roadway (Urushitani et al., 2008). Abou Ezzi suggested that the increased chromogranin A might capture mSOD1, causing it to aggregate in the ER and Golgi, leading to ER stress. Other researchers have shown that motor neurons are especially vulnerable to endoplasmic reticulum stress (see ARF related news story on Saxena et al., 2009), so stressing the ER or secretory pathways could be a common theme in the disease, Julien suggested.

The scientists also crossed the SOD1-G37R mouse with a chromogranin A knockout strain. These double mutants showed little difference in disease phenotype from single SOD1 mutants, perhaps because chromogranin B compensates for the loss of chromogranin A, Julien suggested. However, the double mSOD1/chromogranin A knockout mutants did have more motor axons in the ventral root than their mSOD1 counterparts at a late stage of disease, suggesting reduced motor neuron degeneration.

Do these findings in mice have any bearing on human disease? Julien and colleagues also looked for evidence of chromogranin involvement in people with ALS. They discovered a chromogranin B variant, not yet published, that was present at higher levels in a French ALS population than in controls. This variant appears to be a risk factor for the disease, and to cause onset seven years earlier. “It resembles very much ApoE in Alzheimer’s,” Julien said. The researchers are currently working with cell cultures and mice to decipher the mechanism behind the increased risk.

The research supports current hypotheses about mSOD1’s damaging effects, said Christine Vande Velde of the University of Montréal, who was not involved in the study. “It lends more strength to the idea that misfolded SOD1, if you let it stick around or if you stabilize it, then it is more toxic,” she said.—Amber Dance.


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News Citations

  1. Secretion of SOD1 Mutant Proteins Tied to ALS
  2. ER Struggles in Motor Neurons That Fall to ALS

Paper Citations

  1. . Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosis. Nat Neurosci. 2006 Jan;9(1):108-18. PubMed.
  2. . Chromogranin peptides in amyotrophic lateral sclerosis. Regul Pept. 2009 Jan 8;152(1-3):13-21. PubMed.
  3. . Distribution of chromogranin B-like immunoreactivity in the human hippocampus and its changes in Alzheimer's disease. Acta Neuropathol. 2000 Aug;100(2):205-12. PubMed.
  4. . Different chromogranin immunoreactivity between prion and a-beta amyloid plaque. Neuroreport. 2003 Apr 15;14(5):755-8. PubMed.
  5. . The endoplasmic reticulum-Golgi pathway is a target for translocation and aggregation of mutant superoxide dismutase linked to ALS. FASEB J. 2008 Jul;22(7):2476-87. PubMed.
  6. . A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat Neurosci. 2009 May;12(5):627-36. PubMed.

Further Reading


  1. . Chromogranin B and Secretogranin II in transgenic mice overexpressing human APP751 with the London (V717I) and Swedish (K670M/N671L) mutations and in Alzheimer patients. J Alzheimers Dis. 2008 Mar;13(2):123-35. PubMed.
  2. . Wild-type superoxide dismutase acquires binding and toxic properties of ALS-linked mutant forms through oxidation. J Neurochem. 2007 Jul;102(1):170-8. PubMed.
  3. . Chromogranin A activates diverse pathways mediating inducible nitric oxide expression and apoptosis in primary microglia. Neurosci Lett. 2007 Feb 21;413(3):227-32. PubMed.
  4. . Synergistic amplification of beta-amyloid- and interferon-gamma-induced microglial neurotoxic response by the senile plaque component chromogranin A. Am J Physiol Cell Physiol. 2005 Jan;288(1):C169-75. PubMed.
  5. . Chromogranin peptides in Alzheimer's disease. Exp Gerontol. 2004 Jan;39(1):101-13. PubMed.
  6. . Distribution of chromogranin B-like immunoreactivity in the human hippocampus and its changes in Alzheimer's disease. Acta Neuropathol. 2000 Aug;100(2):205-12. PubMed.
  7. . Activation of group II metabotropic glutamate receptors underlies microglial reactivity and neurotoxicity following stimulation with chromogranin A, a peptide up-regulated in Alzheimer's disease. J Neurochem. 2002 Sep;82(5):1179-91. PubMed.