Neuroprotective Effects of Protein Tyrosine Phosphatase 1B Inhibition against ER Stress-Induced Toxicity

Abstract

Several lines of evidence suggest that endoplasmic reticulum (ER) stress plays a critical role in the pathogenesis of many neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Protein tyrosine phosphatase 1B (PTP1B) is known to regulate the ER stress signaling pathway, but its role in neuronal systems in terms of ER stress remains largely unknown. Here, we showed that rotenone-induced toxicity in human neuroblastoma cell lines and mouse primary cortical neurons was ameliorated by PTP1B inhibition. Moreover, the increase in the level of ER stress markers (eIF2α phosphorylation and PERK phosphorylation) induced by rotenone treatment was obviously suppressed by concomitant PTP1B inhibition. However, the rotenone-induced production of reactive oxygen species (ROS) was not affected by PTP1B inhibition, suggesting that the neuroprotective effect of the PTP1B inhibitor is not associated with ROS production. Moreover, we found that MG132-induced toxicity involving proteasome inhibition was also ameliorated by PTP1B inhibition in a human neuroblastoma cell line and mouse primary cortical neurons. Consistently, downregulation of the PTP1B homologue gene in Drosophila mitigated rotenone- and MG132-induced toxicity. Taken together, these findings indicate that PTP1B inhibition may represent a novel therapeutic approach for ER stress-mediated neurodegenerative diseases.

PTP1B inhibitor alleviates deleterious microglial activation and neuronal injury after ischemic stroke by modulating the ER stress-autophagy axis via PERK signaling in microglia

“…Recent studies have shown that extensive involvement of ER stress in microglial activation causes cerebral injuries in Alzheimer’s disease [ 47 ], spinal cord injuries [ 48 ], and LPS/cocaine-induced neuroinflammation [ 17 , 49 ], and PTP1B has been reported to promote ER stress [ 15 , 16 ]. In the current study, increased PTP1B expression in the ipsilateral cortex was synchronous with the activation of UPR after IR injury [ 24 ], and intracerebroventricular administration of PTP1B inhibitor significantly attenuated IR injury-induced overall ER stress.…”

The overexpression of TDP-43 in astrocytes causes neurodegeneration via a PTP1B-mediated inflammatory response

“…LPS-induced neuroinflammation in microglia is also mitigated by PTP1B inhibition [25]. In addition, a recent study indicated that ER stress-induced neuronal toxicity is dramatically reduced by PTP1B inhibition in Drosophila and mammalian neurons [26]. However, it has never been determined whether PTP1B is implicated in the proinflammatory activation of astrocytes.…”

Homer1a Attenuates Endoplasmic Reticulum Stress-Induced Mitochondrial Stress After Ischemic Reperfusion Injury by Inhibiting the PERK Pathway

“…On the other hand, mitochondria may also have effects on ER stress. Studies showed that the mitochondria and ER stress has crosstalk in many models (Malhotra and Kaufman, 2011 ; Senft and Ronai, 2015 ), and the block of respiratory chain complex with rotenone or antimycin A that leads to mitochondrial dysfunction exerts great effects on ER stress (Lee et al, 2010 ; Jeon et al, 2017 ; Heo et al, 2019 ). Further studies are needed to investigate the effects of mitochondria to ER stress regarding Homer1 protein regulation.…”