Pharmacological reduction of ER stress protects against TDP-43 neuronal toxicity in vivo

Vaccaro, Alexandra; Patten, Shunmoogum A.; Aggad, Dina; Julien, Carl; Maios, Claudia; Kabashi, Edor; Drapeau, Pierre; Parker, J. Alex

doi:10.1016/j.nbd.2013.03.015

Cited by 116 publications

(106 citation statements)

References 47 publications

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“…55 Other studies have indicated the potential role of GBZ in neurodegenerative diseases. 21,56,57 Our results demonstrated that GBZ can also function as an antiviral agent. Previous reports have identified salubrinal, another eIF2α phosphatase GADD34 inhibitor, to inhibit the replication of a number of viruses that include HSV, HCV, EBV, and RSV, [58][59][60] indicating the potential use of GADD34 inhibitors as antiviral agents.…”

Section: Discussionmentioning

confidence: 54%

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

Ishaq

Natarajan

2016

Signal Transduction Insights

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Supraphysiological concentrations (SPCs) of triiodo-l-thyronine (T3) have been used in the treatment of a number of nonviral diseases. However, the signaling mechanisms that regulate the function of T3 at these concentrations and their role in modulating cellular stress pathways and antiviral responses are unknown. Here, we have investigated the effects of SPCs of T3 on integrated stress response (ISR) signaling pathways and the replication of vesicular stomatitis virus (VSV). T3 amplified Poly IC-induced activation of RNA-dependent protein kinase, induced phosphorylation of eIF2α, stress granule (SG) formation, IRE1α phosphorylation, XBP1 splicing, and the expression of stress markers. T3 inhibited VSV replication by modulating SG formation and the expression of stress response markers. ISR activator guanabenz also inhibited VSV replication and amplified T3-induced anti-VSV response. To summarize, we have uncovered novel functions of T3 at SPCs as an activator of ISR signaling pathways and an inhibitor of VSV replication. This study offers a proof of principle of the concept that ISR activating agents like SPC of T3 and guanabenz can be potential antiviral agents.

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Section: Discussionmentioning

confidence: 54%

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

Ishaq

Natarajan

2016

Signal Transduction Insights

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“…We previously developed C. elegans (22) and zebrafish (23) genetic models of ALS that are amenable to testing compounds that can preserve motility and reduce neurodegeneration as an independent way of discovering potential therapeutic agents (24,25). The goal of the current study was to use our drug-screening platform to screen large numbers of compounds in order to identify small molecules with acute effects that could be immediately translated into the clinic using short-term improvement of motor function as a read-out.…”

Section: Introductionmentioning

confidence: 99%

Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis

et al. 2017

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“…We have used these C. elegans ALS models to investigate cellular mechanisms underlying motor neuron degeneration [6][7][8] , as well as for drug discovery [9][10][11] . Given the importance of neuroinflammation to the pathological progression of neurodegeneration, including for ALS 12 , we set out to investigate fundamental immune response signalling in our ALS models.…”

mentioning

confidence: 99%

Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons

Vérièpe

Fossouo²,

Parker

2015

Nat Commun

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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease thought to employ cell non-autonomous mechanisms where neuronal injury engages immune responses to influence disease progression. Here we show that the expression of mutant proteins causative for ALS in Caenorhabditis elegans motor neurons induces an innate immune response via TIR-1/Sarm1. Loss of function mutations in tir-1, associated downstream kinases, and the transcription factor atf-7 all suppress motor neuron degeneration. The neurosecretory proteins UNC-13 and UNC-31 are required for induction of the immune response as well as the degeneration of motor neurons. The human orthologue of UNC-13, UNC13A, has been identified as a genetic modifier of survival in ALS, and we provide functional evidence of UNC-13/UNC13A in regulating motor neuron degeneration. We propose that the innate immune system reacts to the presence of mutant proteins as a contagion, recruiting a pathogen resistance response that is ultimately harmful and drives progressive neurodegeneration.

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Pharmacological reduction of ER stress protects against TDP-43 neuronal toxicity in vivo

Cited by 116 publications

References 47 publications

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

Integrated Stress Response Signaling Pathways Induced by Supraphysiological Concentrations of Thyroid Hormone Inhibit Viral Replication

Neuroleptics as therapeutic compounds stabilizing neuromuscular transmission in amyotrophic lateral sclerosis

Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons

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