Activation of the unfolded protein response in canine degenerative myelopathy. (20th November 2018)

• Record Type: Journal Article
• Authors: Yokota, Shunya; Kobatake, Yui; Noda, Yasuhiro; Nakata, Kohei; Yamato, Osamu; Hara, Hideaki; Sakai, Hiroki; Nishida, Hidetaka; Maeda, Sadatohi; Kamishina, Hiroaki
• Is Part Of: Neuroscience letters. Volume 687(2018)
• Page Start: 216
• Page End: 222
• Publication Date: 2018-11-20
• Subjects: Amyotrophic lateral sclerosis -- Degenerative myelopathy -- Endoplasmic reticulum stress -- Superoxide dismutase 1 -- Unfolded protein response; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2018.09.040
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: There is up-regulated expression of the ER stress marker GRP78/BiP (BiP) in the spinal cords of DM-affected dogs. Reactive astrocytes in the spinal cords of DM-affected dogs express a high level of BiP. Transcriptional analyses of DM spinal tissues demonstrate increased expression levels of ASK1 and XBP1s. E40K-transfected Neuro2A cells expressed higher levels of BiP than wild-type SOD1-transfected cells. Abstract: Canine degenerative myelopathy (DM) is an adult-onset progressive and fatal neurodegenerative disorder. Superoxide dismutase 1 (SOD1) mutations have been reported in affected dogs and immunohistochemical analyses revealed the accumulation of mutant SOD1 (E40K) in spinal neurons and astrocytes. Therefore, this disease is regarded as a unique spontaneous large-animal model of SOD1-mediated amyotrophic lateral sclerosis (ALS) in humans. Recent studies reported that endoplasmic reticulum (ER) stress is a key pathomechanism underlying motor neuron death in ALS. The present study demonstrated the up-regulated expression of the ER stress marker GRP78/BiP (BiP) in the spinal cords of DM-affected dogs. Immunohistochemistry of serial spinal cord sections revealed strong BiP expression in microglia and astrocytes in DM compared to normal control dogs, whereas such difference was not observed in spinal neurons. The results of transcriptional analyses of DM spinal tissues showed increased expression levels of apoptosis signal-regulating kinase 1 (ASK1) and spliced X-box binding protein (XBP1s). E40K-transfected Neuro2A cells expressed higher levels of BiP than wild-type SOD1-transfected cells. These results suggest that the activation of the unfolded protein response (UPR) in microglia and astrocytes plays crucial roles in UPR-mediated inflammation in the spinal cords of DM-affected dogs.