Toxicity from different SOD1 mutants dysregulates the complement system and the neuronal regenerative response in ALS motor neurons
- Ludwig Institute and Departments of Medicine and Neuroscience, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093
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Contributed by Don W. Cleveland, March 10, 2007 (received for review February 5, 2007)
Abstract
Global, age-dependent changes in gene expression from rodent models of inherited ALS caused by dominant mutations in superoxide-dismutase 1 (SOD1) were identified by using gene arrays and RNAs isolated from purified embryonic and adult motor neurons. Comparison of embryonic motor neurons expressing a dismutase active ALS-linked mutant SOD1 with those expressing comparable levels of wild-type SOD1 revealed the absence of mutant-induced mRNA changes. An age-dependent mRNA change that developed presymptomatically in adult motor neurons collected by laser microdissection from mice expressing dismutase active ALS-linked mutants was dysregulation of the d/l-serine biosynthetic pathway, previously linked to both excitotoxic and neurotrophic effects. An unexpected dysregulation common to motor neurons expressing either dismutase active or inactive mutants was induction of neuronally derived components of the classic complement system and the regenerative/injury response. Alteration of these mutant SOD1-induced pathways identified a set of targets for therapies for inherited ALS.
Footnotes
- *To whom correspondence should be addressed. E-mail: dcleveland{at}ucsd.edu
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This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on April 25, 2006.
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Author contributions: C.S.L. and D.W.C. designed research; C.S.L. and S.B. performed research; C.S.L. analyzed data; and C.S.L. and D.W.C. wrote the paper.
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The authors declare no conflict of interest.
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Data deposition: GeneChip raw data (CEL-files) were deposited at http://arrayconsortium.tgen.org (accession nos. lobsi-affy-mouse-193446 and lobsi-affy-rat-194438) and are available through the Gene Expression Omnibus (GEO) Database, www.ncbi.nlm.nih.gov/geo.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0702230104/DC1.
- Abbreviations:
- SOD1,
- Cu/Zn superoxide dismutase 1;
- En,
- embryonic day n.
- © 2007 by The National Academy of Sciences of the USA
