Misfolded SOD1 pathology in sporadic Amyotrophic Lateral Sclerosis

Paré, Bastien; Lehmann, Manuela; Beaudin, Marie; Nordström, Ulrika; Saïkali, Stéphan; Julien, Jean‐Pierre; Gilthorpe, Jonathan; Marklund, Stefan L.; Cashman, Neil R.; Andersen, Peter M.; Forsberg, Karin; Dupré, Nicolas; Gould, Peter; Brännström, Thomas; Gros‐Louis, François

doi:10.1038/s41598-018-31773-z

Cited by 108 publications

(73 citation statements)

References 69 publications

(73 reference statements)

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“…The mutation decreases the folding stability of SOD1, which induces the formation of protein aggregates (Alexianu, Kozovska, & Appel, 2001;Pasinelli & Brown, 2006;Pramatarova, Laganiere, Roussel, Brisebois, & Rouleau, 2001). These protein aggregates play an important role in SOD1-mediated ALS pathogenesis (Watanabe et al, 2001), and wild-type SOD1 aggregates have also been recently linked to sporadic ALS pathology (Forsberg et al, 2019;Pare et al, 2018). A major hallmark of protein aggregates in ALS patients is the presence of TDP-43 (Neumann et al, 2006), which is thought to translocate from the nucleus to the cytoplasm as part of the disease pathogenesis (Barmada et al, 2010).…”

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confidence: 99%

The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins

Deora

Lee

Albornoz

et al. 2019

Glia

157

118

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Microglial NLRP3 inflammasome activation is emerging as a key contributor to neuroinflammation during neurodegeneration. Pathogenic protein aggregates such as β‐amyloid and α‐synuclein trigger microglial NLRP3 activation, leading to caspase‐1 activation and IL‐1β secretion. Both caspase‐1 and IL‐1β contribute to disease progression in the mouse SOD1G93A model of amyotrophic lateral sclerosis (ALS), suggesting a role for microglial NLRP3. Prior studies, however, suggested SOD1G93A mice microglia do not express NLRP3, and SOD1G93A protein generated IL‐1β in microglia independent to NLRP3. Here, we demonstrate using Nlrp3‐GFP gene knock‐in mice that microglia express NLRP3 in SOD1G93A mice. We show that both aggregated and soluble SOD1G93A activates inflammasome in primary mouse microglia leading caspase‐1 and IL‐1β cleavage, ASC speck formation, and the secretion of IL‐1β in a dose‐ and time‐dependent manner. Importantly, SOD1G93A was unable to induce IL‐1β secretion from microglia deficient for Nlrp3, or pretreated with the specific NLRP3 inhibitor MCC950, confirming NLRP3 as the key inflammasome complex mediating SOD1‐induced microglial IL‐1β secretion. Microglial NLRP3 upregulation was also observed in the TDP‐43Q331K ALS mouse model, and TDP‐43 wild‐type and mutant proteins could also activate microglial inflammasomes in a NLRP3‐dependent manner. Mechanistically, we identified the generation of reactive oxygen species and ATP as key events required for SOD1G93A‐mediated NLRP3 activation. Taken together, our data demonstrate that ALS microglia express NLRP3, and that pathological ALS proteins activate the microglial NLRP3 inflammasome. NLRP3 inhibition may therefore be a potential therapeutic approach to arrest microglial neuroinflammation and ALS disease progression.

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confidence: 99%

The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins

Deora

Lee

Albornoz

et al. 2019

Glia

157

118

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“…It has been thought that the majority of patients have accumulation of tar DNA binding protein 43 (TDP-43), (as well as others), with a small group of patients having accumulations of superoxide dismutase 1 (SOD1) (18)(19)(20). However, recent evidence suggests that SOD1 may aggregate in the spinal cord in a majority of ALS patients (21,22). The genes that cause ALS usually encode for proteins or polypeptides that accumulate within cells or are involved in the metabolism of protein aggregates (19,23).…”

Section: Introductionmentioning

confidence: 99%

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

et al. 2020

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Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease that is defined by loss of upper and lower motor neurons, associated with accumulation of protein aggregates in cells. There is also pathology in extra-motor areas of the brain, Possible causes of cell death include failure to deal with the aggregated proteins, glutamate toxicity and mitochondrial failure. ALS also involves abnormalities of metabolism and the immune system, including neuroinflammation in the brain and spinal cord. Strikingly, there are also abnormalities of the peripheral immune system, with alterations of T lymphocytes, monocytes, complement and cytokines in the peripheral blood of patients with ALS. The precise contribution of the peripheral immune system in ALS pathogenesis is an active area of research. Although some trials of immunomodulatory agents have been negative, there is strong preclinical evidence of benefit from immune modulation and further trials are currently underway. Here, we review the emerging evidence implicating peripheral immune alterations contributing to ALS, and their potential as future therapeutic targets for clinical intervention.

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“…There have been reports of misfolded SOD1 pathology detected in sporadic ALS cases using conformation-specific antibodies selective for misfolded SOD1 protein species [37], as well as the absence of misfolded SOD1 in sporadic ALS [38]. In light of the prion-like properties of SOD1 protein [11], the potential contribution of misfolded WT SOD1 protein to ALS pathogenesis and neurotoxicity becomes an interesting topic [36,39].…”

Section: Discussionmentioning

confidence: 99%

The Timing and Extent of Motor Neuron Vulnerability in ALS Correlates with Accumulation of Misfolded SOD1 Protein in the Cortex and in the Spinal Cord

Genç¹,

Gozutok²,

Koçak³

et al. 2020

Cells

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Understanding the cellular and molecular basis of selective vulnerability has been challenging, especially for motor neuron diseases. Developing drugs that improve the health of neurons that display selective vulnerability relies on in vivo cell-based models and quantitative readout measures that translate to patient outcome. We initially developed and characterized UCHL1-eGFP mice, in which motor neurons are labeled with eGFP that is stable and long-lasting. By crossing UCHL1-eGFP to amyotrophic lateral sclerosis (ALS) disease models, we generated ALS mouse models with fluorescently labeled motor neurons. Their examination over time began to reveal the cellular basis of selective vulnerability even within the related motor neuron pools. Accumulation of misfolded SOD1 protein both in the corticospinal and spinal motor neurons over time correlated with the timing and extent of degeneration. This further proved simultaneous degeneration of both upper and lower motor neurons, and the requirement to consider both upper and lower motor neuron populations in drug discovery efforts. Demonstration of the direct correlation between misfolded SOD1 accumulation and motor neuron degeneration in both cortex and spinal cord is important for building cell-based assays in vivo. Our report sets the stage for shifting focus from mice to diseased neurons for drug discovery efforts, especially for motor neuron diseases.

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Misfolded SOD1 pathology in sporadic Amyotrophic Lateral Sclerosis

Cited by 108 publications

References 69 publications

The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins

The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins

The Peripheral Immune System and Amyotrophic Lateral Sclerosis

The Timing and Extent of Motor Neuron Vulnerability in ALS Correlates with Accumulation of Misfolded SOD1 Protein in the Cortex and in the Spinal Cord

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