Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text PDF (Full Text) PPT slides of all figures Supplemental Material Index Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Matsumoto, G. Articles by Morimoto, R. I. Search for Related Content PubMed PubMed Citation Articles by Matsumoto, G. Articles by Morimoto, R. I. Related Collections Related Article Social Bookmarking                      What's this?

Department of Biochemistry, Molecular Biology and Cell Biology, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208

Correspondence to Richard I. Morimoto: r-morimoto{at}northwestern.edu

The appearance of protein aggregates is a characteristic of protein misfolding disorders including familial amyotrophic lateral sclerosis, a neurodegenerative disease caused by inherited mutations in Cu/Zn superoxide dismutase 1 (SOD1). Here, we use live cell imaging of neuronal and nonneuronal cells to show that SOD1 mutants (G85R and G93A) form an aggregate structure consisting of immobile scaffolds, through which noninteracting cellular proteins can diffuse. Hsp70 transiently interacts, in a chaperone activity-dependent manner, with these mutant SOD1 aggregate structures. In contrast, the proteasome is sequestered within the aggregate structure, an event associated with decreased degradation of a proteasomal substrate. Through the use of time-lapse microscopy of individual cells, we show that nearly all (90%) aggregate-containing cells express higher levels of mutant SOD1 and died within 48 h, whereas 70% of cells expressing a soluble mutant SOD1 survived. Our results demonstrate that SOD1 G85R and G93A mutants form a distinct class of aggregate structures in cells destined for neuronal cell death.

Abbreviations used in this paper: fALS, familial amyotrophic lateral sclerosis; FLIP, fluorescent loss in photobleaching; NBT, nitroblue tetrazolium; PI, propidium iodide; RFI, relative fluorescence intensity; ROI, region of interest; SOD1, Cu/Zn superoxide dismutase 1; TBP, TATA-binding protein; WT, wild type.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

Related Article

Contrasts in neuronal aggregates

Nicole LeBrasseur
J. Cell Biol. 2005 171: 8. [Full Text] [PDF]

This article has been cited by other articles:

• Watson, M. R., Lagow, R. D., Xu, K., Zhang, B., Bonini, N. M. (2008). A Drosophila Model for Amyotrophic Lateral Sclerosis Reveals Motor Neuron Damage by Human SOD1. J. Biol. Chem. 283: 24972-24981 [Abstract] [Full Text]  
• Urushitani, M., Ezzi, S. A., Matsuo, A., Tooyama, I., Julien, J.-P. (2008). The endoplasmic reticulum-Golgi pathway is a target for translocation and aggregation of mutant superoxide dismutase linked to ALS. FASEB J. 22: 2476-2487 [Abstract] [Full Text]  
• Witan, H., Kern, A., Koziollek-Drechsler, I., Wade, R., Behl, C., Clement, A. M. (2008). Heterodimer formation of wild-type and amyotrophic lateral sclerosis-causing mutant Cu/Zn-superoxide dismutase induces toxicity independent of protein aggregation. Hum Mol Genet 17: 1373-1385 [Abstract] [Full Text]  
• Shaw, B. F., Lelie, H. L., Durazo, A., Nersissian, A. M., Xu, G., Chan, P. K., Gralla, E. B., Tiwari, A., Hayward, L. J., Borchelt, D. R., Valentine, J. S., Whitelegge, J. P. (2008). Detergent-insoluble Aggregates Associated with Amyotrophic Lateral Sclerosis in Transgenic Mice Contain Primarily Full-length, Unmodified Superoxide Dismutase-1. J. Biol. Chem. 283: 8340-8350 [Abstract] [Full Text]  
• Niwa, J.-i., Yamada, S.-i., Ishigaki, S., Sone, J., Takahashi, M., Katsuno, M., Tanaka, F., Doyu, M., Sobue, G. (2007). Disulfide Bond Mediates Aggregation, Toxicity, and Ubiquitylation of Familial Amyotrophic Lateral Sclerosis-linked Mutant SOD1. J. Biol. Chem. 282: 28087-28095 [Abstract] [Full Text]  
• Teuling, E., Ahmed, S., Haasdijk, E., Demmers, J., Steinmetz, M. O., Akhmanova, A., Jaarsma, D., Hoogenraad, C. C. (2007). Motor Neuron Disease-Associated Mutant Vesicle-Associated Membrane Protein-Associated Protein (VAP) B Recruits Wild-Type VAPs into Endoplasmic Reticulum-Derived Tubular Aggregates. J. Neurosci. 27: 9801-9815 [Abstract] [Full Text]  
• Gal, J., Strom, A.-L., Kilty, R., Zhang, F., Zhu, H. (2007). p62 Accumulates and Enhances Aggregate Formation in Model Systems of Familial Amyotrophic Lateral Sclerosis. J. Biol. Chem. 282: 11068-11077 [Abstract] [Full Text]  
• Chowanadisai, W., Lonnerdal, B., Kelleher, S. L. (2006). Identification of a Mutation in SLC30A2 (ZnT-2) in Women with Low Milk Zinc Concentration That Results in Transient Neonatal Zinc Deficiency. J. Biol. Chem. 281: 39699-39707 [Abstract] [Full Text]  
• Kabuta, T., Suzuki, Y., Wada, K. (2006). Degradation of Amyotrophic Lateral Sclerosis-linked Mutant Cu,Zn-Superoxide Dismutase Proteins by Macroautophagy and the Proteasome. J. Biol. Chem. 281: 30524-30533 [Abstract] [Full Text]  
• Lukas, T. J., Luo, W. W., Mao, H., Cole, N., Siddique, T. (2006). Informatics-assisted Protein Profiling in a Transgenic Mouse Model of Amyotrophic Lateral Sclerosis. Mol. Cell. Proteomics 5: 1233-1244 [Abstract] [Full Text]  
• Furukawa, Y., Fu, R., Deng, H.-X., Siddique, T., O'Halloran, T. V. (2006). From the Cover: Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice. Proc. Natl. Acad. Sci. USA 103: 7148-7153 [Abstract] [Full Text]  
• Matsumoto, G., Kim, S., Morimoto, R. I. (2006). Huntingtin and Mutant SOD1 Form Aggregate Structures with Distinct Molecular Properties in Human Cells. J. Biol. Chem. 281: 4477-4485 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents