Unknown,Transcriptomics,Genomics,Proteomics

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Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS


ABSTRACT: Ubiquitous expression of ALS-causing mutations in superoxide dismutase 1 (SOD1) provoke non-cell autonomous paralytic disease. By combining ribosome affinity purification and high-throughput sequencing, a cascade of mutant SOD1-dependent, cell type-specific changes are now identified. Initial mutant-dependent damage is restricted to motor neurons and includes synapse and metabolic abnormalities, endoplasmic reticulum (ER) stress, and selective activation of the PERK arm of the unfolded protein response. PERK activation correlates with what we identify to be a naturally low level of ER chaperones in motor neurons. Early changes in astrocytes are to genes involved in inflammation and metabolism and that are targets of the PPAR and LXR transcription factors. Dysregulation of myelination and lipid signaling pathways and activation of ETS transcription factors occur in oligodendrocytes only after disease initiation. Thus, pathogenesis involves a temporal cascade of cell type selective damage initiating in motor neurons, with subsequent damage within glia driving disease propagation. Cell type-specific mRNA was purified by ribosome affinity purification from the spinal cord of bacTRAP reporter mice that label selective cell types by EGFP-tagged ribosome RPL10A. Sequencing libraries were prepared from 3-6 biological replicates for each genotype to determine the mutant induced gene expression changes in specific cell types.

ORGANISM(S): Mus musculus

SUBMITTER: Ying Sun 

PROVIDER: E-GEOD-74724 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS.

Sun Shuying S   Sun Ying Y   Ling Shuo-Chien SC   Ferraiuolo Laura L   McAlonis-Downes Melissa M   Zou Yiyang Y   Drenner Kevin K   Wang Yin Y   Ditsworth Dara D   Tokunaga Seiya S   Kopelevich Alex A   Kaspar Brian K BK   Lagier-Tourenne Clotilde C   Cleveland Don W DW  

Proceedings of the National Academy of Sciences of the United States of America 20151130 50


Ubiquitous expression of amyotrophic lateral sclerosis (ALS)-causing mutations in superoxide dismutase 1 (SOD1) provokes noncell autonomous paralytic disease. By combining ribosome affinity purification and high-throughput sequencing, a cascade of mutant SOD1-dependent, cell type-specific changes are now identified. Initial mutant-dependent damage is restricted to motor neurons and includes synapse and metabolic abnormalities, endoplasmic reticulum (ER) stress, and selective activation of the PR  ...[more]

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