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Physiol. Genomics 16: 229-239, 2004. First published November 25, 2003; doi:10.1152/physiolgenomics.00087.2001
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Molecular signature of late-stage human ALS revealed by expression profiling of postmortem spinal cord gray matter

¹ Laboratory of Transcriptional and Immune Regulation, Center for Neurologic Diseases, Brigham and Women’s Hospital, Department of Neurology, Harvard Medical School, Boston 02115
² Bioinformatics and Metabolic Engineering Laboratory, Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge 02139
³ Day Neuromuscular Research Laboratory, Massachusetts General Hospital, Department of Neurology, Harvard Medical School, Boston 02114
⁴ C. S. Kubik Laboratory of Neuropathology, Department of Neuropathology, Massachusetts General Hospital, Harvard Medical School, Boston 02114
⁵ Laboratory of Functional Genomics, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts 02115

Little is known about global gene expression patterns in the human neurodegenerative disease amyotrophic lateral sclerosis (ALS). To address this, we used high-density oligonucleotide microarray technology to compare expression levels of 6,800 genes in postmortem spinal cord gray matter obtained from individuals with ALS as well as normal individuals. Using Fisher discriminant analysis (FDA) and leave-one-out cross-validation (LOOCV), we discerned an ALS-specific signature. Moreover, it was possible to distinguish familial ALS (FALS) from sporadic ALS (SALS) gene expression profiles. Characterization of the specific genes significantly altered in ALS uncovered a pro-inflammatory terminal state. Moreover, we found alterations in genes involved in mitochondrial function, oxidative stress, excitotoxicity, apoptosis, cytoskeletal architecture, RNA transcription and translation, proteasomal function, and growth and signaling. It is apparent from this study that DNA microarray analysis and appropriate bioinformatics can reveal distinct phenotypic changes that underlie the terminal stages of neurodegeneration in ALS.

amyotrophic lateral sclerosis; DNA microarrays; mitochondria; excitotoxicity; apoptosis

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