Spinal Cord Endoplasmic Reticulum Stress Associated with a Microsomal Accumulation of Mutant Superoxide Dismutase-1 in an ALS Model

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 15; pp. 6025 - 6030
• Main Authors: Kikuchi, Hitoshi, Almer, Gabriele, Yamashita, Satoshi, Guégan, Christelle, Nagai, Makiko, Xu, Zuoshang, Sosunov, Alexander A., McKhann, Guy M., Przedborski, Serge
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 11-04-2006
• Subjects: Amyotrophic lateral sclerosis; Animals; Antibodies; Apoptosis; Biological Sciences; Caspase 12; Caspases - metabolism; Cerebellum; Disease course; Endoplasmic Reticulum - pathology; Endoplasmic Reticulum - physiology; Enzymes; Mice; Mice, Transgenic; Microsomes - enzymology; Molecular weight; Motor Neuron Disease - genetics; Motor neurons; Mutation; Neurons; Neurosciences; Polymorphism, Single Nucleotide; Protein folding; Rodents; Signal Transduction; Spinal cord; Spinal Cord - pathology; Spinal Cord - physiopathology; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Transgenic animals
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0509227103

Mutation in superoxide dismutase-1 (SOD1), which is a cause of ALS, alters the folding patterns of this protein. Accumulation of misfolded mutant SOD1 might activate endoplasmic reticulum (ER) stress pathways. Here we show that transgenic mice expressing ALS-linked SOD1 mutants exhibit molecular alterations indicative of a recruitment of ER's signaling machinery. We demonstrate by biochemical and morphological methods that mutant SOD1 accumulates inside the ER, where it forms insoluble high molecular weight species and interacts with the ER chaperone immunoglobulin-binding protein. These alterations are age- and region-specific, because they develop over the course of the disease and occur in the affected spinal cord but not in the nonaffected cerebellum in transgenic mutant SOD1 mice. Our results suggest a toxic mechanism for mutant SOD1 by which this ubiquitously expressed pathogenic protein could affect motor neuron survival and contribute to the selective motor neuronal degeneration in ALS.