The ER mitochondria calcium cycle and ER stress response as therapeutic targets in amyotrophic lateral sclerosis

Tadić, Vedrana; Prell, Tino; Lautenschlaeger, Janin; Großkreutz, Julian

doi:10.3389/fncel.2014.00147

Cited by 104 publications

(81 citation statements)

References 210 publications

(236 reference statements)

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“…The endoplasmic reticulum (ER) stress response and increased levels of oxidative stress are associated with the expression of mutant TDP-43 or FUS proteins in cells 24 . Thus, we investigated whether nlp-29::GFP expression was induced by either ER or oxidative stress.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…SOD1, the first identified ALS gene, has been extensively studied with regard to its role in the pathogenesis of this condition with the use of transgenic mice expressing various ALS-linked mutants of human SOD1 (Vinsant et al 2013). Such studies have revealed various mitochondrial abnormalities in these mice, including impairment of ATP permeation through the mitochondrial outer membrane, membrane hyperpolarization, and disturbance of mitochondrial Ca 2+ flow, which is functionally connected to Ca 2+ signaling in the endoplasmic reticulum (Tadic et al 2014;Tan et al 2014) (Fig. 2j).…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

“…S1R is a receptor with chaperone-like activity in the endoplasmic reticulum and regulates Ca 2+ release from this organelle into mitochondria (Hayashi and Su 2007). It has also been implicated in other acute and chronic neurodegenerative disorders (Tadic et al 2014). Intriguingly, a defect in the selective uptake of Ca 2+ into mitochondria has been identified in the end-stage of ALS in SOD1(G93A) transgenic mice (Fuchs et al 2013).…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

Compromised MAPK signaling in human diseases: an update

2015

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The mitogen-activated protein kinases (MAPKs) in mammals include c-Jun NH2-terminal kinase (JNK), p38 MAPK, and extracellular signal-regulated kinase (ERK). These enzymes are serine-threonine protein kinases that regulate various cellular activities including proliferation, differentiation, apoptosis or survival, inflammation, and innate immunity. The compromised MAPK signaling pathways contribute to the pathology of diverse human diseases including cancer and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The JNK and p38 MAPK signaling pathways are activated by various types of cellular stress such as oxidative, genotoxic, and osmotic stress as well as by proinflammatory cytokines such as tumor necrosis factor-α and interleukin 1β. The Ras-Raf-MEK-ERK signaling pathway plays a key role in cancer development through the stimulation of cell proliferation and metastasis. The p38 MAPK pathway contributes to neuroinflammation mediated by glial cells including microglia and astrocytes, and it has also been associated with anticancer drug resistance in colon and liver cancer. We here summarize recent research on the roles of MAPK signaling pathways in human diseases, with a focus on cancer and neurodegenerative conditions.

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“…In fact, mitochondria are located where high amounts of ATP are required (34) and also where Ca 2 + signaling needs tight regulation (126). Importantly, alterations in mitochondrial Ca 2 + have been related to several pathologies, including neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) (318), and aging (332). In recent years, it has been demonstrated that mitochondria actively interact with ER membranes through structuredenominated mitochondria-associated membranes, which enable direct and rapid exchange of lipids and Ca 2 + between the two compartments.…”

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confidence: 99%

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

Apostolova

Víctor

2015

Antioxidants & Redox Signaling

234

147

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Mitochondrial function and specifically its implication in cellular redox/oxidative balance is fundamental in controlling the life and death of cells, and has been implicated in a wide range of human pathologies. In this context, mitochondrial therapeutics, particularly those involving mitochondria-targeted antioxidants, have attracted increasing interest as potentially effective therapies for several human diseases. For the past 10 years, great progress has been made in the development and functional testing of molecules that specifically target mitochondria, and there has been special focus on compounds with antioxidant properties. In this review, we will discuss several such strategies, including molecules conjugated with lipophilic cations (e.g., triphenylphosphonium) or rhodamine, conjugates of plant alkaloids, amino-acid-and peptide-based compounds, and liposomes. This area has several major challenges that need to be confronted. Apart from antioxidants and other redox active molecules, current research aims at developing compounds that are capable of modulating other mitochondria-controlled processes, such as apoptosis and autophagy. Multiple chemically different molecular strategies have been developed as delivery tools that offer broad opportunities for mitochondrial manipulation. Additional studies, and particularly in vivo approaches under physiologically relevant conditions, are necessary to confirm the clinical usefulness of these molecules. Antioxid. Redox Signal. 22, 686-729.

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The ER mitochondria calcium cycle and ER stress response as therapeutic targets in amyotrophic lateral sclerosis

Cited by 104 publications

References 210 publications

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

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

Compromised MAPK signaling in human diseases: an update

Molecular Strategies for Targeting Antioxidants to Mitochondria: Therapeutic Implications

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