Prion Properties of SOD1 in Amyotrophic Lateral Sclerosis and Potential Therapy

Sibilla, Caroline; Bertolotti, Anne

doi:10.1101/cshperspect.a024141

Cited by 30 publications

(25 citation statements)

References 58 publications

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“…In SOD1 mutant-mediated ALS progression, the heterodimer form of the normal and mutated SOD1, which generates oligomers in neurons via the exposed cross-linked disulfide bonds, could be a more serious cause in neuronal damages [52]. The failed nuclear translocation of SOD1WT is consistent with other studies, reporting that the pathogenic process of ALS has very similar characteristics as prion disease progression [53,54]. A normal prion protein PrP C could transit into the misfolded pathogenic form PrP Sc without gene mutation.…”

Section: Discussionsupporting

confidence: 84%

Cytoplasmic Restriction of Mutated SOD1 Impairs the DNA Repair Process in Spinal Cord Neurons

Song²,

Moh³

et al. 2019

Cells

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Amyotrophic lateral sclerosis (ALS) caused by mutation of superoxide dismutase 1 (SOD1), affects various cellular processes and results in the death of motor neurons with fatal defects. Currently, several neurological disorders associated with DNA damage are known to directly induce neurodegenerative diseases. In this research, we found that cytoplasmic restriction of SOD1G93A, which inhibited the nucleic translocation of SOD1WT, was directly related to increasing DNA damage in SOD1- mutated ALS disease. Our study showed that nucleic transport of DNA repair- processing proteins, such as p53, APEX1, HDAC1, and ALS- linked FUS were interfered with under increased endoplasmic reticulum (ER) stress in the presence of SOD1G93A. During aging, the unsuccessful recognition and repair process of damaged DNA, due to the mislocalized DNA repair proteins might be closely associated with the enhanced susceptibility of DNA damage in SOD1- mutated neurons. In addition, the co-expression of protein disulphide isomerase (PDI) directly interacting with SOD1 protein in neurons enhances the nucleic transport of cytoplasmic- restricted SOD1G93A. Therefore, our results showed that enhanced DNA damage by SOD1 mutation-induced ALS disease and further suggested that PDI could be a strong candidate molecule to protect neuronal apoptosis by reducing DNA damage in ALS disease.

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Section: Discussionsupporting

confidence: 84%

Cytoplasmic Restriction of Mutated SOD1 Impairs the DNA Repair Process in Spinal Cord Neurons

Song²,

Moh³

et al. 2019

Cells

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“…K E Y W O R D S glia, IL-1β, innate immunity, motor neuron disease 1 | INTRODUCTION Amyotrophic lateral sclerosis (ALS) is an adult-onset, progressive neurodegenerative disease caused by the deterioration of motor neurons within motor cortex, brain stem, and spinal cord (Lee et al, 2017;Paez-Colasante, Figueroa-Romero, Sakowski, Goutman, & Feldman, 2015;Sibilla & Bertolotti, 2017). Current therapies for ALS are inadequate.…”

mentioning

confidence: 99%

The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins

Deora

Lee

Albornoz

et al. 2019

Glia

156

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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“…Importantly, the induced SOD1 aggregates persisted within cells when the original pathogenic seed was no longer present (Grad et al 2011;Münch et al 2011). Therefore, the newly induced aggregates can act as new misfolding templates and show properties consistent with prion-like propagation (see Sibilla and Bertolotti 2017). Curiously, human misfolded SOD1 is not a competent template for mouse SOD1, an observation that was attributed to a single amino-acid difference between the human and mouse protein position 32 (Grad et al 2011), pointing to a likely interacting region for this conformational conversion.…”

Section: Pathogenic Mechanismsmentioning

confidence: 99%

Biological Spectrum of Amyotrophic Lateral Sclerosis Prions

Polymenidou

Cleveland

2017

Cold Spring Harb Perspect Med

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Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD) are two neurodegenerative diseases with distinct clinical features but common genetic causes and neuropathological signatures. Ten years after the RNA-binding protein TDP-43 was discovered as the main protein in the cytoplasmic inclusions that characterize ALS and FTLD, their pathogenic mechanisms have never seemed more complex. Indeed, discoveries of the past decade have revolutionized our understanding of these diseases, highlighting their genetic heterogeneity and the involvement of protein-RNA assemblies in their pathogenesis. Importantly, these assemblies serve as the foci of protein misfolding and mature into insoluble structures, which further recruit native proteins, turning them into misfolded forms. This self-perpetuating mechanism is a twisted version of classical prion replication that leads to amplification of pathological protein complexes that spread throughout the neuraxis, offering a pathogenic principle that underlies the rapid disease progression that characterizes ALS and FTLD.

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Prion Properties of SOD1 in Amyotrophic Lateral Sclerosis and Potential Therapy

Cited by 30 publications

References 58 publications

Cytoplasmic Restriction of Mutated SOD1 Impairs the DNA Repair Process in Spinal Cord Neurons

Cytoplasmic Restriction of Mutated SOD1 Impairs the DNA Repair Process in Spinal Cord Neurons

The microglial NLRP3 inflammasome is activated by amyotrophic lateral sclerosis proteins

Biological Spectrum of Amyotrophic Lateral Sclerosis Prions

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