EphrinB2 knockdown in cervical spinal cord preserves diaphragm innervation in a mutant SOD1 mouse model of ALS

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by motor neuron loss. Importantly, non-neuronal cell types such as astrocytes also play significant roles in disease pathogenesis. However, mechanisms of astrocyte contribution to ALS remain incompletely understood. Astrocyte involvement suggests that transcellular signaling may play a role in disease. We examined contribution of transmembrane signaling molecule ephrinB2 to ALS pathogenesis, in particular its role in driving motor neuron damage by spinal cord astrocytes. In symptomatic SOD1G93A mice (a well-established ALS model), ephrinB2 expression was dramatically increased in ventral horn astrocytes. Reducing ephrinB2 selectively in these cervical spinal cord astrocytes via viral-mediated shRNA delivery reduced motor neuron loss and preserved respiratory function by maintaining phrenic motor neuron innervation of diaphragm. EphrinB2 expression was also elevated in human ALS spinal cord. These findings implicate ephrinB2 upregulation as both a transcellular signaling mechanism underlying astrocyte pathogenicity in mutant SOD1-associated ALS and a promising therapeutic target.

Identification of key genes and signaling pathway in the pathogenesis of Huntington's disease via bioinformatics and next generation sequencing data analysis

“…Recent studies have shown that SERPINA1 [563], LRRK2 [522], CHRNA4 [564], CD22 [565], TF (transferrin) ssociated tyrosine kinase) [579], FGF14 [580], INSC (INSC spindle orientation adaptor protein) [581], BARHL1 [582], PRKCH (protein kinase C eta) [583], SLC24A4 [584], TMEM176B [585], MBP (myelin basic protein) [586], ACAN (aggrecan) [587], SHH (sonic hedgehog signaling molecule) [588], SIRT2 [589], RBP4 [590], ISM1 [591], HOXB6 [592], CDH13 [593], NTF3 [594], TRPC6 [595], MMP3 [596], HLA-DRB5 [597], HLA-DRB1 [546], CD74 [598], VWF (von Willebrand factor) [599], MDGA1 [600], ANGPT2 [601], NEDD4L [602], CASP1 [603], CHRNA5 [604], CCND2 [605], BRCA2 [606], TET1 [607], ZBTB20 [608], OAS1 [609], EGFR (epidermal growth factor receptor) [610], ABCA1 [611], PLXNA4 [612], FOXG1 [613], WEE1 [433], MAP1B [614], ANK1 [615], GRM3 [436], COMT (catechol-O-methyltransferase) [616], SLC10A4 [617], GPR39 [618] and LIFR (LIF receptor subunit alpha) [562] could promote Alzheimer’s disease progression. SERPINA1 [619], LRRK2 [620], CHRNA4 [621], TLR2 [622], MOBP (myelin associated oligodendrocyte basic protein) [623], AATK (apoptosis associated tyrosine kinase) [624], MBP (myelin basic protein) [625], SHH (sonic hedgehog signaling molecule) [626], XDH (xanthine dehydrogenase) [627], RBP4 [628], GRIA2 [629], NR3C2 [630], HLA-DRB5 [631], HLA-DRA [631], NEDD4L [632], CASP1 [633], EFNB2 [634], CYP7B1 [635], EGFR (epidermal growth factor receptor) [636], MAP1B [637], GRM3 [638<...…”