Intercellular Prion-Like Conversion and Transmission of Cu/Zn Superoxide Dismutase (SOD1) in Cell Culture

Grad, Leslie I.; Pokrishevsky, Edward; Cashman, Neil R.

doi:10.1007/978-1-4939-7244-9_24

Cited by 3 publications

(3 citation statements)

References 11 publications

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“…Cytosolic Cu-Zn-superoxide dismutase (SOD-1) is a ubiquitous cytosolic homodimeric isoenzyme that scavenges and catalyzes the dismutation of superoxide radicals [ 261 ]. Several variants of familial neurodegenerative disorder amyotrophic lateral sclerosis have been linked with SOD-1 mutations, affecting metal-binding sites occupied by Cu 2+ and Zn 2+ and leading to distorted SOD-1–SOD-1 interactions, leading to formation of insoluble aggregates described above [ 262 ]—a phenomenon that can also be propagated from cell to cell [ 263 ]. Intriguingly, many large DNA viruses, including chordopoxviruses [ 264 ], entomopoxviruses [ 265 ], and baculoviruses [ 266 ], encode catalytically inert SOD-1 decoy homologs.…”

Section: Resultsmentioning

confidence: 99%

Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates

Monette

Mouland

2020

Viruses

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Liquid-liquid phase separation (LLPS) is a rapidly growing research focus due to numerous demonstrations that many cellular proteins phase-separate to form biomolecular condensates (BMCs) that nucleate membraneless organelles (MLOs). A growing repertoire of mechanisms supporting BMC formation, composition, dynamics, and functions are becoming elucidated. BMCs are now appreciated as required for several steps of gene regulation, while their deregulation promotes pathological aggregates, such as stress granules (SGs) and insoluble irreversible plaques that are hallmarks of neurodegenerative diseases. Treatment of BMC-related diseases will greatly benefit from identification of therapeutics preventing pathological aggregates while sparing BMCs required for cellular functions. Numerous viruses that block SG assembly also utilize or engineer BMCs for their replication. While BMC formation first depends on prion-like disordered protein domains (PrLDs), metal ion-controlled RNA-binding domains (RBDs) also orchestrate their formation. Virus replication and viral genomic RNA (vRNA) packaging dynamics involving nucleocapsid (NC) proteins and their orthologs rely on Zinc (Zn) availability, while virus morphology and infectivity are negatively influenced by excess Copper (Cu). While virus infections modify physiological metal homeostasis towards an increased copper to zinc ratio (Cu/Zn), how and why they do this remains elusive. Following our recent finding that pan-retroviruses employ Zn for NC-mediated LLPS for virus assembly, we present a pan-virus bioinformatics and literature meta-analysis study identifying metal-based mechanisms linking virus-induced BMCs to neurodegenerative disease processes. We discover that conserved degree and placement of PrLDs juxtaposing metal-regulated RBDs are associated with disease-causing prion-like proteins and are common features of viral proteins responsible for virus capsid assembly and structure. Virus infections both modulate gene expression of metalloproteins and interfere with metal homeostasis, representing an additional virus strategy impeding physiological and cellular antiviral responses. Our analyses reveal that metal-coordinated virus NC protein PrLDs initiate LLPS that nucleate pan-virus assembly and contribute to their persistence as cell-free infectious aerosol droplets. Virus aerosol droplets and insoluble neurological disease aggregates should be eliminated by physiological or environmental metals that outcompete PrLD-bound metals. While environmental metals can control virus spreading via aerosol droplets, therapeutic interference with metals or metalloproteins represent additional attractive avenues against pan-virus infection and virus-exacerbated neurological diseases.

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Section: Resultsmentioning

confidence: 99%

Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates

Monette

Mouland

2020

Viruses

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“… 106 , 107 , 129 Furthermore, in cell culture, expression of other pathogenic proteins such as FUS and TDP-43 induces wildtype SOD1 misfolding that can be transmitted to naïve cells in a prion-like fashion. 85 , 141 …”

Section: Introductionmentioning

confidence: 99%

“…At its N-terminus, TDP-43 is composed of a dimerization domain (N-terminal domain), a nuclear-localized sequence and two RNA recognition motifs (RRMs). 110 , 141 , 142 The C-terminal part has two IDRs and a glycine-rich domain involved in multivalent weak intermolecular interactions. 115 Like other proteins containing IDRs, also called prion-like domains, TDP-43 is well known to self-assemble and creates a separate phase in membrane-less compartments like stress granules ( Fig.…”

Section: Introductionmentioning

confidence: 99%

Prionoids in amyotrophic lateral sclerosis

Gosset

Camu

Raoul

et al. 2022

Brain Communications

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Amyotrophic lateral sclerosis (ALS) is the third most frequent neurodegenerative disease after Alzheimer’s and Parkinson’s disease. ALS is characterized by the selective and progressive loss of motoneurons in the spinal cord, brainstem, and cerebral cortex. Clinical manifestations typically occur in midlife and start with focal muscle weakness, followed by the rapid and progressive wasting of muscles and subsequent paralysis. As with other neurodegenerative diseases, the condition typically begins at an initial point and then spreads along neuroanatomical tracts. This feature of disease progression suggests the spreading of prion-like proteins called prionoids in the affected tissues, which is similar to the spread of prion observed in Creutzfeldt-Jakob disease. Intensive research over the last decade has proposed the ALS-causing gene products SOD1, TDP-43, and FUS as very plausible prionoids contributing to the spread of the pathology. In this review, we will discuss the molecular and cellular mechanisms leading to the propagation of these prionoids in ALS.

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Targeting RACK1 to alleviate TDP-43 and FUS proteinopathy-mediated suppression of protein translation and neurodegeneration

Zhao,

Cowan,

Coutts

et al. 2023

acta neuropathol commun

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TAR DNA-binding protein 43 (TDP-43) and Fused in Sarcoma/Translocated in Sarcoma (FUS) are ribonucleoproteins associated with pathogenesis of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Under physiological conditions, TDP-43 and FUS are predominantly localized in the nucleus, where they participate in transcriptional regulation, RNA splicing and metabolism. In disease, however, they are typically mislocalized to the cytoplasm where they form aggregated inclusions. A number of shared cellular pathways have been identified that contribute to TDP-43 and FUS toxicity in neurodegeneration. In the present study, we report a novel pathogenic mechanism shared by these two proteins. We found that pathological FUS co-aggregates with a ribosomal protein, the Receptor for Activated C-Kinase 1 (RACK1), in the cytoplasm of spinal cord motor neurons of ALS, as previously reported for pathological TDP-43. In HEK293T cells transiently transfected with TDP-43 or FUS mutant lacking a functional nuclear localization signal (NLS; TDP-43ΔNLS and FUSΔNLS), cytoplasmic TDP-43 and FUS induced co-aggregation with endogenous RACK1. These co-aggregates sequestered the translational machinery through interaction with the polyribosome, accompanied by a significant reduction of global protein translation. RACK1 knockdown decreased cytoplasmic aggregation of TDP-43ΔNLS or FUSΔNLS and alleviated associated global translational suppression. Surprisingly, RACK1 knockdown also led to partial nuclear localization of TDP-43ΔNLS and FUSΔNLS in some transfected cells, despite the absence of NLS. In vivo, RACK1 knockdown alleviated retinal neuronal degeneration in transgenic Drosophila melanogaster expressing hTDP-43WT or hTDP-43Q331K and improved motor function of hTDP-43WT flies, with no observed adverse effects on neuronal health in control knockdown flies. In conclusion, our results revealed a novel shared mechanism of pathogenesis for misfolded aggregates of TDP-43 and FUS mediated by interference with protein translation in a RACK1-dependent manner. We provide proof-of-concept evidence for targeting RACK1 as a potential therapeutic approach for TDP-43 or FUS proteinopathy associated with ALS and FTLD.

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Intercellular Prion-Like Conversion and Transmission of Cu/Zn Superoxide Dismutase (SOD1) in Cell Culture

Cited by 3 publications

References 11 publications

Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates

Zinc and Copper Ions Differentially Regulate Prion-Like Phase Separation Dynamics of Pan-Virus Nucleocapsid Biomolecular Condensates

Prionoids in amyotrophic lateral sclerosis

Targeting RACK1 to alleviate TDP-43 and FUS proteinopathy-mediated suppression of protein translation and neurodegeneration

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