Targeting the deNEDDylating enzyme NEDP1 to ameliorate ALS phenotypes through Stress Granules dissolution

Kassouf, Toufic; Shrivastava, Rohit; Meszka, Igor; Bailly, Aymeric; Polanowska, Jolanta; Trauchessec, Hélène; Mandrioli, Jessica; Carra, Serena; Xirodimas, Dimitris P.

doi:10.1101/2023.01.06.522988

Cited by 3 publications

(3 citation statements)

References 68 publications

(122 reference statements)

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“…The mechanistic association between ALS and TBI has been investigated using animals including Drosophila [61,77] and rodent models of disease [78][79][80][81][82]. In some of these instances, TBI has been shown to cause stress granule formation, altered N/C transport dynamics, and TDP-43 mis-localization independent of genetic background [46,60,61,78,82], pathologies that have been documented in ALS patients [38,40,41,[83][84][85][86][87][88]. Moreover, while there are other reports of utilizing iPSC technologies to model TBI mechanisms in vitro [89][90][91][92] our approach represents the first to combine ALS patient specific iPSC-derived neurons with a traumatic injury infliction.…”

Section: Discussionmentioning

confidence: 99%

Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derivedC9orf72-associated ALS/FTD motor neurons

Martin,

Santacruz,

Mitevska

et al. 2024

Preprint

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A hexanucleotide repeat expansion (HRE) inC9orf72is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, patients with the HRE exhibit a wide disparity in clinical presentation and age of symptom onset suggesting an interplay between genetic background and environmental stressors. Neurotrauma as a result of traumatic brain or spinal cord injury has been shown to increase the risk of ALS/FTD in epidemiological studies. Here, we combine patient-specific induced pluripotent stem cells (iPSCs) with a custom-built device to deliver biofidelic stretch trauma toC9orf72patient and isogenic control motor neurons (MNs)in vitro. We find that mutant but not control MNs exhibit selective degeneration after a single incident of severe trauma, which can be partially rescued by pretreatment with aC9orf72antisense oligonucleotide. A single incident of mild trauma does not cause degeneration but leads to cytoplasmic accumulation of TDP-43 inC9orf72MNs. This mislocalization, which only occurs briefly in isogenic controls, is eventually restored inC9orf72MNs after 6 days. Lastly, repeated mild trauma ablates the ability of patient MNs to recover. These findings highlight alterations in TDP-43 dynamics inC9orf72ALS/FTD patient MNs following traumatic injury and demonstrate that neurotrauma compounds neuropathology inC9orf72ALS/FTD. More broadly, our work establishes anin vitroplatform that can be used to interrogate the mechanistic interactions between ALS/FTD and neurotrauma.

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Section: Discussionmentioning

confidence: 99%

Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derivedC9orf72-associated ALS/FTD motor neurons

Martin,

Santacruz,

Mitevska

et al. 2024

Preprint

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“…Inhibition of NEDP1, a specific deconjugating enzyme of ubiquitinlike molecule NEDD8, accelerates pathological SG disassembly by deNEDDylation of PARP-1, which improves ALS phenotypes in cells and nematodes. 135 Olaparib, a PARP inhibitor, suppresses PARylation of hnRNPA1 and TDP-43, which may suppress SG assembly by regulate their LLPS. This pharmacological inhibition of PARP improves hnRNPA1 and TDP-43-induced neurotoxicity in cell and fly models of ALS.…”

Section: Post-translational Modificationsmentioning

confidence: 99%

Targeting stress granules in neurodegenerative diseases: A focus on biological function and dynamics disorders

Fang,

Liu,

Huang

et al. 2023

BioFactors

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Stress granules (SGs) are membraneless organelles formed by eukaryotic cells in response to stress to promote cell survival through their pleiotropic cytoprotective effects. SGs recruit a variety of components to enhance their physiological function, and play a critical role in the propagation of pathological proteins, a key factor in neurodegeneration. Recent advances indicate that SG dynamic disorders exacerbate neuronal susceptibility to stress in neurodegenerative diseases (NDs) including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Huntington's disease (HD) and Parkinson's disease (PD). Here, we outline the biological functions of SGs, highlight SG dynamic disorders in NDs, and emphasize therapeutic approaches for enhancing SG dynamics to provide new insights into ND intervention.

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“…The assembly and disassembly of SGs are tightly regulated processes in response to and relief from stress, respectively 3 . Implicated in tumorigenesis, neurodegeneration, and antiviral innate immunity, elucidating the mechanisms underlying SG formation could offer new therapeutic avenues for various diseases [4][5][6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

PARP10 is Critical for Stress Granule Initiation

Jayabalan,

Bhambhani,

L Leung

2023

Preprint

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Stress granules (SGs) are cytoplasmic biomolecular condensates enriched with RNA, translation factors, and other proteins. They form in response to stress and are implicated in various diseased states including viral infection, tumorigenesis, and neurodegeneration. Understanding the mechanism of SG assembly, particularly its initiation, offers potential therapeutic avenues. Although ADP-ribosylation plays a key role in SG assembly, and one of its key forms—poly(ADP-ribose) or PAR—is critical for recruiting proteins to SGs, the specific enzyme responsible remains unidentified. Here, we systematically knock down the human ADP-ribosyltransferase family and identify PARP10 as pivotal for SG assembly. Live-cell imaging reveals PARP10’s crucial role in regulating initial assembly kinetics. Further, we pinpoint the core SG component, G3BP1, as a PARP10 substrate and find that PARP10 regulates SG assembly driven by both G3BP1 and its modeled mechanism. Intriguingly, while PARP10 only adds a single ADP-ribose unit to proteins, G3BP1 is PARylated, suggesting its potential role as a scaffold for protein recruitment. PARP10 knockdown alters the SG core composition, notably decreasing translation factor presence. Based on our findings, we propose a model in which ADP-ribosylation acts as a rate-limiting step, initiating the formation of this RNA-enriched condensate.HIGHLIGHTSPARP10 plays a crucial role in the initial SG assembly kinetics.The core SG component G3BP1 is a substrate of PARP10.PARP10 is required for SG assembly mediated by G3BP1 or its synthetic mimic.PARP10 knockdown reduces the levels of translation factors within the SG core.

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Targeting the deNEDDylating enzyme NEDP1 to ameliorate ALS phenotypes through Stress Granules dissolution

Cited by 3 publications

References 68 publications

Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derivedC9orf72-associated ALS/FTD motor neurons

Traumatic injury causes selective degeneration and TDP-43 mislocalization in human iPSC-derivedC9orf72-associated ALS/FTD motor neurons

Targeting stress granules in neurodegenerative diseases: A focus on biological function and dynamics disorders

PARP10 is Critical for Stress Granule Initiation

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