ALS-Associated E478G Mutation in Human OPTN (Optineurin) Promotes Inflammation and Induces Neuronal Cell Death

Liu, Zhengzhao; Li, Hongming; Hong, Chengyu; Chen, Menglu; Tao, Yue; Chen, Chunyuan; Wang, Zhenxing; You, Qing; Li, Chuanyin; Weng, Qinjie; Xie, Hui; Hu, Ronggui

doi:10.3389/fimmu.2018.02647

Cited by 36 publications

(61 citation statements)

References 44 publications

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“…Besides, mutations are suggested to activate the inflammatory factors, which also contribute to disease progression. 177 As found in recent studies, OPTN will translocate to damaged mitochondria, which is dependent on Parkin ubiquitination of mitochondria. 175 169,183,184 In addition, VCP also exhibits some properties similar to OPTN;…”

Section: Optn/tbk1mentioning

confidence: 68%

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Mechanisms and roles of mitophagy in neurodegenerative diseases

2019

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Mitochondria are double‐membrane‐encircled organelles existing in most eukaryotic cells and playing important roles in energy production, metabolism, Ca 2+ buffering, and cell signaling. Mitophagy is the selective degradation of mitochondria by autophagy. Mitophagy can effectively remove damaged or stressed mitochondria, which is essential for cellular health. Thanks to the implementation of genetics, cell biology, and proteomics approaches, we are beginning to understand the mechanisms of mitophagy, including the roles of ubiquitin‐dependent and receptor‐dependent signals on damaged mitochondria in triggering mitophagy. Mitochondrial dysfunction and defective mitophagy have been broadly associated with neurodegenerative diseases. This review is aimed at summarizing the mechanisms of mitophagy in higher organisms and the roles of mitophagy in the pathogenesis of neurodegenerative diseases. Although many studies have been devoted to elucidating the mitophagy process, a deeper understanding of the mechanisms leading to mitophagy defects in neurodegenerative diseases is required for the development of new therapeutic interventions, taking into account the multifactorial nature of diseases and the phenotypic heterogeneity of patients.

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Section: Optn/tbk1mentioning

confidence: 68%

“…Moreover, OPTN mutations have been shown in previous studies to enhance NF‐κB activity and impede intracellular transport. Besides, mutations are suggested to activate the inflammatory factors, which also contribute to disease progression …”

Section: Mitophagy and Neurodegenerative Diseasesmentioning

confidence: 99%

Mechanisms and roles of mitophagy in neurodegenerative diseases

2019

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“…One group initially reported that OPTN −/− mice had a slight increase in proinflammatory cytokines, dysmyelination and deficits in vertical rearing activity, but other studies reported no neuroinflammation, dysmyelination and/or neurological defects ( Ito et al , 2016 ; Slowicka et al , 2016 ; Dermentzaki et al , 2019 ). However, an ubiquitin-binding optineurin patient mutation (E478G) lentivirally delivered to the mouse motor cortex, triggered secretion of proinflammatory cytokines and neuronal death ( Liu et al , 2018 ). Therefore, although most studies dismissed excessive inflammation as a mechanism of action of OPTN mutations in ALS, additional functional studies will be necessary to understand if individual OPTN mutations such as E478G act by distinct pathogenic mechanisms.…”

Section: How Does Immunity Turn From Friend To Foe During Als?mentioning

confidence: 99%

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Béland

Markovinović

Jakovac

et al. 2020

Brain Communications

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Despite wide genetic, environmental and clinical heterogeneity in amyotrophic lateral sclerosis, a rapidly fatal neurodegenerative disease targeting motoneurons, neuroinflammation is a common finding. It is marked by local glial activation, T cell infiltration and systemic immune system activation. The immune system has a prominent role in the pathogenesis of various chronic diseases, hence some of them, including some types of cancer, are successfully targeted by immunotherapeutic approaches. However, various anti-inflammatory or immunosuppressive therapies in amyotrophic lateral sclerosis have failed. This prompted increased scrutiny over the immune-mediated processes underlying amyotrophic lateral sclerosis. Perhaps the biggest conundrum is that amyotrophic lateral sclerosis pathogenesis exhibits features of three otherwise distinct immune dysfunctions –excessive inflammation, autoimmunity and inefficient immune responses. Epidemiological and genome-wide association studies show only minimal overlap between amyotrophic lateral sclerosis and autoimmune diseases, so excessive inflammation is usually thought to be secondary to protein aggregation, mitochondrial damage or other stresses. In contrast, several recently characterized amyotrophic lateral sclerosis-linked mutations, including those in TBK1, OPTN, CYLD and C9orf72, could lead to inefficient immune responses and/or damage pile-up, suggesting that an innate immunodeficiency may also be a trigger and/or modifier of this disease. In such cases, nonselective immunosuppression would further restrict neuroprotective immune responses. Here we discuss multiple layers of immune-mediated neuroprotection and neurotoxicity in amyotrophic lateral sclerosis. Particular focus is placed on individual patient mutations that directly or indirectly affect the immune system, and the mechanisms by which these mutations influence disease progression. The topic of immunity in amyotrophic lateral sclerosis is timely and relevant, because it is one of the few common and potentially malleable denominators in this heterogenous disease. Importantly, amyotrophic lateral sclerosis progression has recently been intricately linked to patient T cell and monocyte profiles, as well as polymorphisms in cytokine and chemokine receptors. For this reason, precise patient stratification based on immunophenotyping will be crucial for efficient therapies.

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“…The E478G mutation in the UBAN of OPTN abolishes its NF-κB suppressive activity 23 , as residues involved in linear ubiquitin-binding correspond to the residues crucial for keeping NF-κB inactive 24 . The mutations result in significant up-regulation of IL-1β, causing neuroinflammation and neuronal cell death of motor neurons, leading to Amyotrophic Lateral Sclerosis 25 .…”

Section: Discussionmentioning

confidence: 99%

Distribution of disease-causing germline mutations in coiled-coils implies an important role of their N-terminal region

Kálmán

Mészáros

Gáspári

et al. 2020

Sci Rep

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Next-generation sequencing resulted in the identification of a huge number of naturally occurring variations in human proteins. The correct interpretation of the functional effects of these variations necessitates the understanding of how they modulate protein structure. Coiled-coils are α-helical structures responsible for a diverse range of functions, but most importantly, they facilitate the structural organization of macromolecular scaffolds via oligomerization. In this study, we analyzed a comprehensive set of disease-associated germline mutations in coiled-coil structures. Our results suggest an important role of residues near the N-terminal part of coiled-coil regions, possibly critical for superhelix assembly and folding in some cases. We also show that coiled-coils of different oligomerization states exhibit characteristically distinct patterns of disease-causing mutations. Our study provides structural and functional explanations on how disease emerges through the mutation of these structural motifs.

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ALS-Associated E478G Mutation in Human OPTN (Optineurin) Promotes Inflammation and Induces Neuronal Cell Death

Cited by 36 publications

References 44 publications

Mechanisms and roles of mitophagy in neurodegenerative diseases

Mechanisms and roles of mitophagy in neurodegenerative diseases

Immunity in amyotrophic lateral sclerosis: blurred lines between excessive inflammation and inefficient immune responses

Distribution of disease-causing germline mutations in coiled-coils implies an important role of their N-terminal region

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