Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Proc Natl Acad Sci U S A. 2015 Dec 15;112(50):E6993-7002. doi: 10.1073/pnas.1520639112. Epub 2015 Nov 30.

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

Author information

1
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
2
The Research Institute at Nationwide Children's Hospital, Department of Neuroscience, The Ohio State University, Columbus, OH 43205;
3
Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093;
4
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093; Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093.
5
Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093; Department of Neurosciences, University of California at San Diego, La Jolla, CA 92093 dcleveland@ucsd.edu.

Abstract

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 PRKR-like ER kinase (PERK) arm of the unfolded protein response. PERK activation correlates with what we identify as a naturally low level of ER chaperones in motor neurons. Early changes in astrocytes occur in genes that are involved in inflammation and metabolism and are targets of the peroxisome proliferator-activated receptor and liver X receptor 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.

KEYWORDS:

ALS; RNA profiling; SOD1; bacTRAP; cell type selective toxicity

PMID:
26621731
PMCID:
PMC4687558
DOI:
10.1073/pnas.1520639112
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center