Antiviral Immune Response as a Trigger of FUS Proteinopathy in Amyotrophic Lateral Sclerosis

Shelkovnikova, Tatyana A.; An, Haiyan; Skelt, Lucy; Tregoning, John S.; Humphreys, Ian R.; Buchman, Vladimir L.

doi:10.1016/j.celrep.2019.11.094

Cited by 32 publications

(38 citation statements)

References 78 publications

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“…Then, it is plausible that HSV-2 latently infected neurons may express higher levels of TDP-43 and Fus in response to the presence of LAT. In line with this hypothesis, bioinformatics predict several binding sites for TDP-43 and Fus in the LAT sequence (not shown), and curiously, a recent report suggests antiviral responses may trigger Fus aggregation [73].…”

Section: Discussionsupporting

confidence: 53%

Analysis of ALS-related proteins during herpes simplex virus-2 latent infection

Cabrera

Rodriguez-Izquierdo

Jiménez

et al. 2020

J Neuroinflammation

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Background Genetics have provided hints on potential molecular pathways involved in neurodegenerative diseases (NDD). However, the number of cases caused exclusively by genetic alterations is low, suggesting an important contribution of environmental factors to NDDs. Among these factors, viruses like herpes simplex viruses (HSV-2), capable of establishing lifelong infections within the nervous system (NS), are being proposed to have a role in NDDs. Despite promising data, there is a significant lack of knowledge on this and an urgent need for more research. Methods We have set up a mouse model to study HSV latency and its associated neuroinflammation in the spinal cord. The goal of this model was to observe neuroinflammatory changes caused by HSV latent infections, and if those changes were similar to alterations observed in the spinal cord of amyotrophic lateral sclerosis (ALS) patients. Results In infected spinal cords, we have observed a strong leukocyte infiltration and a severe alteration of microglia close to motor neurons. We have also analyzed ALS-related proteins: we have not found changes in TDP-43 and Fus in neurons, but interestingly, we have found decreased protein levels of C9orf72, of which coding gene is severely altered in some familial forms of ALS and is critical for microglia homeostasis. Conclusions Latent infection of HSV in the spinal cord showed altered microglia and leukocyte infiltration. These inflammatory features resembled to those observed in the spinal cord of ALS patients. No changes mimicking ALS neuropathology, such as TDP-43 cytoplasmic inclusions, were found in infected spinal cords, but a decrease in protein levels of C9orf72 was observed. Then, further studies should be required to determine whether HSV-2 has a role in ALS.

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Section: Discussionsupporting

confidence: 53%

Analysis of ALS-related proteins during herpes simplex virus-2 latent infection

Cabrera

Rodriguez-Izquierdo

Jiménez

et al. 2020

J Neuroinflammation

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“…Another DNA/RNA-binding protein, fused in sarcoma (FUS) also acts as a co-activator of NF-κB, and expression of disease-associated FUS mutation (R521G) in astrocytes led to a tumour necrosis factor (TNF)-induced motoneuron death, which could be rescued by NF-κB inhibition ( Uranishi et al , 2001 ; Kia et al , 2018 ). Moreover, viral infection causes mutant FUS aggregation ( Shelkovnikova et al , 2019 ). In addition to these aggregate-prone proteins, numerous other genes mutated in ALS such as p62/SQSTM1 , TBK1 , OPTN , ALS2 , CHMP2B , C9orf72 and CYLD were reported to disrupt proteostasis at the level of proteasomal or autophagosomal degradation, and could therefore indirectly facilitate aggregation and trigger inflammation ( Fig.…”

Section: Als Genetics and Mechanismsmentioning

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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“…In addition, enteroviral and encephalomyelitis infections have been shown to trigger aggregation of TDP-43 in mouse models [79,80]. By analogy, aggregation of FUS has also recently been shown to be initiated on viral infections [81]. Thus, it is tempting to speculate that a MPC coopted by viruses may be involved in ALS pathogenesis.…”

Section: Retroviruses and Alsmentioning

confidence: 99%