Activating Transcription Factor-6α Deletion Modulates the Endoplasmic Reticulum Stress Response after Spinal Cord Injury but Does Not Affect Locomotor Recovery

Ohri, Sujata Saraswat; Mullins, Ashley; Hetman, Michał; Whittemore, Scott R.

doi:10.1089/neu.2015.3993

Cited by 14 publications

(8 citation statements)

References 26 publications

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“…PERK, ATF6, and IRE-1, all three arms of the ER stress response signaling pathway, are all known to be activated after SCI 31 . It also has been found that ablation of ATF6 does not affect locomotor recovery after spinal cord injury; and attenuation of PERK is a viable therapeutic target to improve functional recovery after SCI 32 , 33 . The function of IRE-1 inhibition in spinal cord injury has not been determined.…”

Section: Resultsmentioning

confidence: 99%

TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress

et al. 2020

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Background and Aim: Increasing evidence suggests that spinal cord injury (SCI)-induced defects in autophagic flux may contribute to an impaired ability for neurological repair following injury. Transcription factor E3 (TFE3) plays a crucial role in oxidative metabolism, lysosomal homeostasis, and autophagy induction. Here, we investigated the role of TFE3 in modulating autophagy following SCI and explored its impact on neurological recovery. Methods: Histological analysis via HE, Nissl and Mason staining, survival rate analysis, and behavioral testing via BMS and footprint analysis were used to determine functional recovery after SCI. Quantitative real-time polymerase chain reaction, Western blotting, immunofluorescence, TUNEL staining, enzyme-linked immunosorbent assays, and immunoprecipitation were applied to examine levels of autophagy flux, ER-stress-induced apoptosis, oxidative stress, and AMPK related signaling pathways. In vitro studies using PC12 cells were performed to discern the relationship between ROS accumulation and autophagy flux blockade. Results: Our results showed that in SCI, defects in autophagy flux contributes to ER stress, leading to neuronal death. Furthermore, SCI enhances the production of reactive oxygen species (ROS) that induce lysosomal dysfunction to impair autophagy flux. We also showed that TFE3 levels are inversely correlated with ROS levels, and increased TFE3 levels can lead to improved outcomes. Finally, we showed that activation of TFE3 after SCI is partly regulated by AMPK-mTOR and AMPK-SKP2-CARM1 signaling pathways. Conclusions: TFE3 is an important regulator in ROS-mediated autophagy dysfunction following SCI, and TFE3 may serve as a promising target for developing treatments for SCI.

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Section: Resultsmentioning

confidence: 99%

TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress

et al. 2020

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“…Models of mechanical damage, such as occurs in NIHL, have implicated the UPR in neurons. In a study of crushed optic nerves, treatment of mice with ISRIB reduced axonal degeneration 17 , and UPR modulation improved recovery after spinal cord injury in mice 18 . Our work in genetic and noise-induced mouse models has similarly demonstrated a role for ER Ca 2+ dysregulation as a link between acoustic overstimulation and UPR activation 4 .…”

Section: Discussionmentioning

confidence: 99%

Integrated Stress Response Inhibition Provides Sex-Dependent Protection Against Noise-Induced Cochlear Synaptopathy

Rouse

Matthews

Li³

et al. 2020

Preprint

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Noise-induced hearing loss (NIHL) is a common health concern with significant social, psychological, and cognitive implications. Moderate levels of acoustic overstimulation associated with tinnitus and impaired speech perception cause cochlear synaptopathy, characterized physiologically by reduction in wave I of the suprathreshold auditory brainstem response (ABR) and reduced number of synapses between sensory hair cells and auditory neurons. The unfolded protein response (UPR), an endoplasmic reticulum stress response pathway, has been implicated in the pathogenesis and treatment of NIHL as well as neurodegeneration and synaptic damage in the brain. In this study, we used the small molecule UPR modulator ISRIB (Integrated Stress Response InhiBitor) to treat noise-induced cochlear synaptopathy in a mouse model. Mice pretreated with ISRIB prior to noise-exposure were protected against noise-induced synapse loss. Male, but not female, mice also exhibited ISRIB-mediated protection against noise-induced suprathreshold ABR wave-I amplitude reduction. Female mice had higher baseline wave-I amplitudes but greater sensitivity to noise-induced wave-I reduction. Our results suggest that the UPR is implicated in noise-induced cochlear synaptopathy, and can be targeted for treatment.

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“…In addition, the activation of ATF6 branch of the UPR was also reported to improve the outcomes after cerebral ischemia( Yu et al, 2018 ). On the contrary, it has been demonstrated in a rat model of spinal cord injury, that knockout of ATF6 could protect against ER stress and promote oligodendrocyte precursor cell survival ( Saraswat et al, 2018 ). Actually, the activation of ATF6 branch of UPR has dual roles in the regulation of cell survival.…”

Section: Discussionmentioning

confidence: 99%

Melatonin Protects Against Neuronal Apoptosis via Suppression of the ATF6/CHOP Pathway in a Rat Model of Intracerebral Hemorrhage

Lü

Zheng

et al. 2018

Front. Neurosci.

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Neuronal apoptosis is an important factor accounting for the poor outcomes of intracerebral hemorrhage (ICH). This study first showed that inhibition of activating transcription factor 6 (ATF6) could alleviate secondary brain injury through anti-apoptosis after ICH in rats. Melatonin, ATF6 and CCAAT/enhancer-binding protein homologous protein (CHOP) siRNAs were applied in this study. Brain edema, neurological functions, blood-brain barrier (BBB) integrity were evaluated at 24 h after ICH. Western blot analysis was used to evaluate the protein level of target proteins (ATF6, CHOP, Bip, Bcl-2, Bax, and cleaved caspase-3). Reverse transcription-polymerase chain reaction (RT-PCR) was used to assess the mRNA level of ATF6, CHOP and cleaved caspase-3. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and caspase-3 immunofluorescence staining were applied to evaluate the neuronal cell death. The results suggested that the levels of ATF6 and its downstream protein, CHOP, were upregulated and reached the peak at 24 h after ICH. ATF6 was highly expressed in neurons. The administration of melatonin significantly decreased the mRNA and protein levels of ATF6, and its downstream targets, CHOP and cleaved caspase-3, but increased the Bcl-2/Bax ratio, which ameliorated the neurological functions. The CHOP siRNA significantly reversed the pro-apoptotic effect induced by the increased ATF6 level after ICH. Melatonin could protect against neuronal apoptosis via suppression of ATF6/CHOP arm of ER-stress-response pathway.

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Activating Transcription Factor-6α Deletion Modulates the Endoplasmic Reticulum Stress Response after Spinal Cord Injury but Does Not Affect Locomotor Recovery

Cited by 14 publications

References 26 publications

TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress

TFE3, a potential therapeutic target for Spinal Cord Injury via augmenting autophagy flux and alleviating ER stress

Integrated Stress Response Inhibition Provides Sex-Dependent Protection Against Noise-Induced Cochlear Synaptopathy

Melatonin Protects Against Neuronal Apoptosis via Suppression of the ATF6/CHOP Pathway in a Rat Model of Intracerebral Hemorrhage

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