Activation of microglial neuregulin1 signaling in the corticospinal tracts of ALS patients with upper motor neuron signs.
We recently found neuregulin1 (NRG1) receptors are activated on microglia in the ventral horn of both ALS patients and SOD1 mice, suggesting a common pathological mechanism. However, it is not clear whether this signaling system also plays a role in patients with upper motor neuron (UMN) features, where patients show significant pathological changes in the corticospinal tracts (CSTs). Since the connection between upper and lower motor neuron (LMN) systems in ALS patients is not readily seen in the SOD1 mouse, we examined the lateral and ventral CSTs for NRG1 receptor activation and NRG1 expression in ALS patients with UMN symptoms compared to control patients with no evidence of neurodegenerative disease. We found that ALS patients with UMN symptoms showed increased microglial activation that colocalized with NRG1 receptor activation in the lateral and ventral CSTs. These same regions also showed increased NRG1 protein expression locally but no change in NRG1 mRNA. In conclusion, these data suggest that increased NRG1 protein accumulation could contribute to UMN disease through microglial activation in the CSTs.
Hiller ALS Center.
Fei
F
Song
Pohung
P
Chiang
John
J
Ravits
Jeffrey A
JA
Loeb
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000150:complications* / Q000473:pathology*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D017628:Microglia / Q000378:metabolism*; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000209:etiology*; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009186:Myelin Sheath / Q000473:pathology; D011712:Pyramidal Tracts / Q000473:pathology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D013482:Superoxide Dismutase / Q000235:genetics; D000072105:Superoxide Dismutase-1; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D008565:Membrane Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C046375:NRSN1 protein, human; C000606290:SOD1 protein, human; C000606291:Sod1 protein, mouse