Author:
Sun Shuying,Sun Ying,Ling Shuo-Chien,Ferraiuolo Laura,McAlonis-Downes Melissa,Zou Yiyang,Drenner Kevin,Wang Yin,Ditsworth Dara,Tokunaga Seiya,Kopelevich Alex,Kaspar Brian K.,Lagier-Tourenne Clotilde,Cleveland Don W.
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.
Funder
HHS | NIH | National Institute of Neurological Disorders and Stroke
Publisher
Proceedings of the National Academy of Sciences
Cited by
151 articles.
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