Nature Neuroscience 9, 108 - 118 (2005)
Published online: 20 December 2005; | doi:10.1038/nn1603
Chromogranin-mediated secretion of mutant superoxide dismutase proteins linked to amyotrophic lateral sclerosisMakoto Urushitani1, Attila Sik2, Takashi Sakurai3, Nobuyuki Nukina3, Ryosuke Takahashi4
& Jean-Pierre Julien11
Department of Anatomy and Physiology, Laval University, Centre de Recherche du Centre Hospitalier de l' Université Laval, 2705 boulevard Laurier, Sainte-Foy, Quebec G1V 4G2, Canada. 2
Department of Psychiatry, Centre de Recherche Université Laval Robert-Giffard, 2601 de la Canardiere, Quebec, Quebec G1J 2G3, Canada. 3
Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan. 4
Motor System Neurodegeneration, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
Correspondence should be addressed to Jean-Pierre Julien jean-pierre.julien@crchul.ulaval.ca 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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