Optineurin Dysfunction in Amyotrophic Lateral Sclerosis: Why So Puzzling?

Prtenjača, Nikolina; Dominović, Marin; Peradinović, Josip; Šajn, Rozalija; Markovinović, Andrea; Munitić, Ivana

doi:10.18054/pb.v121-122i1-2.10627

Cited by 4 publications

(3 citation statements)

References 4 publications

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“…Briefly, the mechanisms involved are thought to arise from loss-of-function mutations that may affect inflammation via the nuclear factor-κB (NF-κB) and/or interferon regulatory factor 3 (IRF-3) pathways [ 31 , 35 , 36 ]. However, the exact pathogenic mechanisms are still inconclusive due to discrepancies arising from different experimental models [ 37 ].…”

Section: Als and Ftd Genetics Epigenetics And Mechanismsmentioning

confidence: 99%

Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder

De Marchi,

Franjkic,

Schito

et al. 2023

Biomedicines

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Proteinopathy and neuroinflammation are two main hallmarks of neurodegenerative diseases. They also represent rare common events in an exceptionally broad landscape of genetic, environmental, neuropathologic, and clinical heterogeneity present in patients. Here, we aim to recount the emerging trends in amyotrophic lateral sclerosis (ALS) and frontotemporal degeneration (FTD) spectrum disorder. Our review will predominantly focus on neuroinflammation and systemic immune imbalance in ALS and FTD, which have recently been highlighted as novel therapeutic targets. A common mechanism of most ALS and ~50% of FTD patients is dysregulation of TAR DNA-binding protein 43 (TDP-43), an RNA/DNA-binding protein, which becomes depleted from the nucleus and forms cytoplasmic aggregates in neurons and glia. This, in turn, via both gain and loss of function events, alters a variety of TDP-43-mediated cellular events. Experimental attempts to target TDP-43 aggregates or manipulate crosstalk in the context of inflammation will be discussed. Targeting inflammation, and the immune system in general, is of particular interest because of the high plasticity of immune cells compared to neurons.

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Section: Als and Ftd Genetics Epigenetics And Mechanismsmentioning

confidence: 99%

Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder

De Marchi,

Franjkic,

Schito

et al. 2023

Biomedicines

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show abstract

“…Optineurin specifically binds to methionine 1- and lysine 63-linked polyubiquitin chains via its C-terminal ubiquitin-binding region 17 – 19 . It has been reported to regulate several cellular processes, including inflammatory signalling, autophagy, vesicle trafficking, and cell death, but the precise role of optineurin mutations in ALS and/or FTD pathogenesis is still unclear as it differs in distinct experimental settings 20 . Several mouse models investigated the role of optineurin in neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

Neuroimmune characterization of optineurin insufficiency mouse model during ageing

Prtenjača¹,

Peradinović²,

Markovinović³

et al. 2023

Sci Rep

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Optineurin is a multifunctional polyubiquitin-binding protein implicated in inflammatory signalling. Optineurin mutations are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), neurodegenerative diseases characterised by neuronal loss, neuroinflammation, and peripheral immune disbalance. However, the pathogenic role of optineurin mutations is unclear. We previously observed no phenotype in the unmanipulated young optineurin insufficiency mice (Optn470T), designed to mimic ALS/FTD-linked truncations deficient in polyubiquitin binding. The purpose of this study was to investigate whether ageing would trigger neurodegeneration. We performed a neurological, neuropathological, and immunological characterization of ageing wild-type (WT) and Optn470T mice. No motor or cognitive differences were detected between the genotypes. Neuropathological analyses demonstrated signs of ageing including lipofuscin accumulation and microglial activation in WT mice. However, this was not worsened in Optn470T mice, and they did not exhibit TAR DNA-binding protein 43 (TDP-43) aggregation or neuronal loss. Spleen immunophenotyping uncovered T cell immunosenescence at two years but without notable differences between the WT and Optn470T mice. Conventional dendritic cells (cDC) and macrophages exhibited increased expression of activation markers in two-year-old Optn470T males but not females, although the numbers of innate immune cells were similar between genotypes. Altogether, a combination of optineurin insufficiency and ageing did not induce ALS/FTD-like immune imbalance and neuropathology in mice.

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“…Optineurin specifically binds to methionine 1-and lysine 63-linked polyubiquitin chains via its C-terminal ubiquitin-binding region (16)(17)(18). It has been reported to regulate several cellular processes, including inflammatory signalling, autophagy, vesicle trafficking, and cell death, but the precise role of optineurin mutations in ALS and/or FTD pathogenesis is puzzling and has been shown to vary in different experimental settings (20). Several mouse models were generated to investigate the role of optineurin in neurodegeneration.…”

Section: Introductionmentioning

confidence: 99%

Neuroimmune characterization of optineurin insufficiency mouse model during ageing

Prtenjača

Peradinović

Markovinović

et al. 2023

Preprint

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Optineurin is a multifunctional polyubiquitin-binding protein implicated in inflammatory signalling. Optineurin mutations are associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), neurodegenerative diseases characterised by neuronal loss, neuroinflammation, and peripheral immune disbalance. However, the pathogenic role of optineurin mutations is unclear. We previously observed no phenotype in the unmanipulated young optineurin insufficiency mice (Optn470T), designed to mimic ALS/FTD-linked truncations deficient in polyubiquitin binding. The purpose of this study was to investigate whether ageing would trigger neurodegeneration. We performed a neuroimmune characterization of ageing wild-type (WT) and Optn470T mice. No motor or cognitive differences were detected between the genotypes. Neuropathological analyses demonstrated signs of ageing including lipofuscin accumulation and microglial activation. However, this was not worsened in Optn470T mice, and they did not exhibit TAR DNA-binding protein 43 (TDP-43) aggregation or neuronal loss. Spleen immunophenotyping uncovered T cell immunosenescence at two years but without notable differences between the WT and Optn470T mice. Conventional dendritic cells (cDC) and macrophages exhibited increased expression of activation markers in two-year-old Optn470T males but not females, although the numbers of innate immune cells were similar between genotypes. Altogether, a combination of optineurin insufficiency and ageing did not induce ALS/FTD-like neuropathology in mice.

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Optineurin Dysfunction in Amyotrophic Lateral Sclerosis: Why So Puzzling?

Cited by 4 publications

References 4 publications

Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder

Emerging Trends in the Field of Inflammation and Proteinopathy in ALS/FTD Spectrum Disorder

Neuroimmune characterization of optineurin insufficiency mouse model during ageing

Neuroimmune characterization of optineurin insufficiency mouse model during ageing

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