Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Transcription profiling of human post mortem spinal cord grey matter from sporadic and familial ALS patients vs controls to identify amyotrophic lateral sclerosis (ALS) associated genes

ABSTRACT: Identification of amyotrophic lateral sclerosis (ALS) associated genes. Post mortem spinal cord grey matter from sporadic and familial ALS patients compared with controls.

ORGANISM(S): Homo sapiens

DISEASE(S): sporadic ALS

SUBMITTER: Fernando Dangond

PROVIDER: E-GEOD-833 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Molecular signature of late-stage human ALS revealed by expression profiling of postmortem spinal cord gray matter.

Dangond Fernando F 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

Physiological genomics 20040115 2

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. Moreove ...[more]

PMID: 14645737

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Project description:Increasing evidence suggests synaptic dysfunction is a central and possibly triggering factor in Amyotrophic Lateral Sclerosis (ALS). Despite this, we still know very little about the molecular profile of an ALS synapse. To address this gap, we designed a synaptic proteomics experiment to perform an unbiased assessment of the synaptic proteome in the ALS brain. We isolated synaptoneurosomes from fresh-frozen postmortem human cortex (11 controls and 18 ALS) and stratified the ALS group based on cognitive profile (Edinburgh Cognitive and Behavioural ALS Screen (ECAS score)) and presence of a C9ORF72 hexanucleotide repeat expansion (C9ORF72 -RE). This allowed us to assess regional differences and the impact of phenotype and genotype on the synaptic proteome, using Tandem Mass Tagging-based proteomics. We identified over 6000 proteins in our synaptoneurosomes and using robust bioinformatics analysis we validated the strong enrichment of synapses. We found more than 30 ALS-associated proteins in synaptoneurosomes, including TDP-43, FUS, SOD1 and C9ORF72. We identified almost 500 proteins with altered expression levels in ALS, with region-specific changes highlighting proteins and pathways with intriguing links to neurophysiology and pathology. Stratifying the ALS cohort by cognitive status revealed almost 150 specific alterations in cognitively impaired ALS synaptic preparations. Stratifying by C9ORF72 -RE status revealed 330 protein alterations in the C9ORF72 -RE+ve group, with KEGG pathway analysis highlighting strong enrichment for postsynaptic dysfunction, related to glutamatergic receptor signalling. We have validated some of these changes by western blot and at a single synapse level using array tomography imaging. In summary, we have generated the first unbiased map of the human ALS synaptic proteome, revealing novel insight into this key compartment in ALS pathophysiology and highlighting the influence of cognitive decline and C9ORF72 -RE on synaptic composition.

Dataset Information

Transcription profiling of human post mortem spinal cord grey matter from sporadic and familial ALS patients vs controls to identify amyotrophic lateral sclerosis (ALS) associated genes

Publications

Molecular signature of late-stage human ALS revealed by expression profiling of postmortem spinal cord gray matter.

Similar Datasets

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