Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Translational profiling identifies a cascade of damage initiated in motor neurons and spreading to glia in mutant SOD1-mediated ALS. 2662 31

Neuromuscular junction (NMJ) disruption is an early pathogenic event in amyotrophic lateral sclerosis (ALS). Yet, direct links between NMJ pathways and ALS-associated genes such as FUS, whose heterozygous mutations cause aggressive forms of ALS, remain elusive. In a knock-in Fus-ALS mouse model, we identified postsynaptic NMJ defects in newborn homozygous mutants that were attributable to mutant FUS toxicity in skeletal muscle. Adult heterozygous knock-in mice displayed smaller neuromuscular endplates that denervated before motor neuron loss, which is consistent with 'dying-back' neuronopathy. FUS was enriched in subsynaptic myonuclei, and this innervation-dependent enrichment was distorted in FUS-ALS. Mechanistically, FUS collaborates with the ETS transcription factor ERM to stimulate transcription of acetylcholine receptor genes. Co-cultures of induced pluripotent stem cell-derived motor neurons and myotubes from patients with FUS-ALS revealed endplate maturation defects due to intrinsic FUS toxicity in both motor neurons and myotubes. Thus, FUS regulates acetylcholine receptor gene expression in subsynaptic myonuclei, and muscle-intrinsic toxicity of ALS mutant FUS may contribute to dying-back motor neuronopathy.
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PMID:FUS-mediated regulation of acetylcholine receptor transcription at neuromuscular junctions is compromised in amyotrophic lateral sclerosis. 3159 61