Molecular signature of late-stage human ALS revealed by expression profiling of postmortem spinal cord gray matter.
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 approximately 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.
Dangond
Fernando
F
Laboratory of Transcriptional and Immune Regulation, Center for Neurologic Diseases, Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Hwang
Daehee
D
Camelo
Sandra
S
Pasinelli
Piera
P
Frosch
Matthew P
MP
Stephanopoulos
Gregory
G
Stephanopoulos
George
G
Brown
Robert H
RH
Gullans
Steven R
SR
D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000378:metabolism; D016002:Discriminant Analysis; D020869:Gene Expression Profiling; D018698:Glutamic Acid / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology; D009097:Multienzyme Complexes / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger / Q000378:metabolism*; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism* / Q000473:pathology; D014158:Transcription, Genetic
D009097:Multienzyme Complexes; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; D012333:RNA, Messenger; D018698:Glutamic Acid; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex