Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD

Fang, Mark Y.; Markmiller, Sebastian; Vu, Anthony Q.; Javaherian, Ashkan; Dowdle, William E.; Jolivet, Philippe; Bushway, Paul J.; Castello, Nicholas A.; Baral, Ashmita; Chan, Michelle Y.; Linsley, Jeremy W.; Linsley, Drew; Mercola, Mark; Finkbeiner, Steven; Lécuyer, Éric; Lewcock, Joseph W.; Yeo, G

doi:10.1016/j.neuron.2019.05.048

Cited by 174 publications

(159 citation statements)

References 80 publications

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“…This is in contrast to what we and other groups previously described in immortalized cell lines where localization of TDP-43 in SG occurred under sub-lethal stress conditions [5,11]. The different response to stress of primary and immortalized cells is also supported by a recent paper showing that TDP-43 is recruited into SG after 24-hour puromycin treatment in mTDP-43 N352S and FUS R521G iPSC-motoneurons [26].…”

Section: Discussionsupporting

confidence: 55%

“…Nonetheless, recent findings indicate that, even if they appear as distinct entities, a mechanistic link between SG and pathological TDP-43 inclusions may occur [23][24][25][26]. A missing point in this scenario is the evidence that TDP-43 pathology directly arises from SG, partly due to the experimental sub-lethal stress conditions used so far in several studies to induce SG formation.…”

Section: Introductionmentioning

confidence: 99%

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Induction Of Chronic Stress Reveals An Interplay Of Stress Granules And TDP-43 Pathological Aggregates In Human ALS Fibroblasts And iPSC-Neurons

Gumina

Lenzi

Bossolasco

et al. 2020

Preprint

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases characterized by the presence of neuropathological aggregates of phosphorylated TDP-43 (P-TDP-43). The RNAbinding protein TDP-43 is also a component of stress granules (SG), cytoplasmic foci forming to arrest translation under sub-lethal stress conditions. Although commonly considered as distinct structures, a link between SG and pathological TDP-43 inclusions may occur despite evidence that TDP-43 pathology directly arises from SG is still under debate. Primary fibroblasts and iPSC-derived neurons (iPSC-N) from ALS patients carrying mutations in TARDBP (n=3) and C9ORF72 (n=3) genes and from healthy controls (n=3) were exposed to oxidative stress by sodium arsenite. SG formation and cell response to stress was evaluated and quantified by immunofluorescence and electron microscopy analyses. We found that, not only an acute, but also a chronic oxidative insult, better mimicking a persistent condition of stress as in neurodegeneration, is able to induce SG formation in primary fibroblasts and iPSC-N. Importantly, only upon chronic stress, we observed TDP-43 recruitment into SG and the formation of distinct P-TDP-43 aggregates, very similar to the abnormal inclusions observed in ALS/FTD autoptic brains. Moreover, in fibroblasts, cell response to stress was different in control compared with mutant ALS cells, probably due to their different vulnerability. A quantitative analysis revealed also differences in terms of number of SG-forming cells and SG size, suggesting a different composition of foci in acute and chronic stress. In condition of prolonged stress, SG and P-TDP-43 aggregate formation was concomitant with p62 increase and autophagy dysregulation in both ALS fibroblasts and iPSC-N, as confirmed by immunofluorescence and ultrastructural analyses. We found that exposure to a chronic oxidative insult promotes the formation of both SG and P-TDP-43 aggregates in patient-derived cells, reinforcing the idea that SG fail to properly disassemble, interfering with the protein quality control system. Moreover, we obtained a disease cell model recapitulating ALS/FTD P-TDP-43 aggregates, which represents an invaluable bioassay to study TDP-43 pathology and develop therapeutic strategies aimed at disaggregating or preventing the formation of pathological inclusions.

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Induction Of Chronic Stress Reveals An Interplay Of Stress Granules And TDP-43 Pathological Aggregates In Human ALS Fibroblasts And iPSC-Neurons

Gumina

Lenzi

Bossolasco

et al. 2020

Preprint

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“…A hallmark of ALS includes the mislocalization of nuclear TDP-43 to cytoplasmic inclusions in spinal MNs of ALS patients (Bentmann et al, 2012;Blokhuis et al, 2013;Farg et al, 2013;Keller et al, 2012;Kim et al, 2013;Liu-Yesucevitz et al, 2010). MNs derived from ALS patients in both our study and previous studies exhibited prolonged cytoplasmic accumulation of TDP-43 following recovery from puromycin stress compared with MNs derived from healthy individuals (Fang et al, 2019). As a result, we next examined if AdoMet treatment affected TDP-43 recruitment to SGs in addition to decreasing the number of SGs that form.…”

Section: Adomet Affects Sg Fusion In Cultured Mammalian Cellsmentioning

confidence: 69%

Conserved metabolite regulation of stress granule assembly via AdoMet

Begovich

Yeo

et al. 2020

Journal of Cell Biology

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Stress granules (SGs) are evolutionarily conserved condensates of ribonucleoproteins that assemble in response to metabolic stresses. Because aberrant SG formation is associated with amyotrophic lateral sclerosis (ALS), understanding the connection between metabolic activity and SG composition can provide therapeutic insights into neurodegeneration. Here, we identify 17 metabolic enzymes recruited to yeast SGs in response to physiological growth stress. Furthermore, the product of one of these enzymes, AdoMet, is a regulator of SG assembly and composition. Decreases in AdoMet levels increase SG formation, while chronic elevation of AdoMet produces SG remnants lacking proteins associated with the 5′ end of transcripts. Interestingly, acute elevation of AdoMet blocks SG formation in yeast and motor neurons. Treatment of ALS-derived motor neurons with AdoMet also suppresses the formation of TDP-43–positive SGs, a hallmark of ALS. Together, these results argue that AdoMet is an evolutionarily conserved regulator of SG composition and assembly with therapeutic potential in neurodegeneration.

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“…Recent studies demonstrate that methods to control condensate assembly or properties harbor therapeutic potential. High‐content screening has identified small molecules that modulate SG assembly, prevent accumulation of aggregation‐prone proteins in SGs and block protein aggregation and rescue neurodegenerative phenotypes . Moreover, a HSP104‐based disaggregase has been shown to attenuate phase separation of EWS‐FLI and FUS‐CHOP and reduce their toxicity in yeast models .…”

Section: Resultsmentioning

confidence: 99%

Biomolecular condensates in neurodegeneration and cancer

Spannl

Tereshchenko

Mastromarco

et al. 2019

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The intracellular environment is partitioned into functionally distinct compartments containing specific sets of molecules and reactions. Biomolecular condensates, also referred to as membrane‐less organelles, are diverse and abundant cellular compartments that lack membranous enclosures. Molecules assemble into condensates by phase separation; multivalent weak interactions drive molecules to separate from their surroundings and concentrate in discrete locations. Biomolecular condensates exist in all eukaryotes and in some prokaryotes, and participate in various essential house‐keeping, stress‐response and cell type‐specific processes. An increasing number of recent studies link abnormal condensate formation, composition and material properties to a number of disease states. In this review, we discuss current knowledge and models describing the regulation of condensates and how they become dysregulated in neurodegeneration and cancer. Further research on the regulation of biomolecular phase separation will help us to better understand their role in cell physiology and disease.

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Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD

Cited by 174 publications

References 80 publications

Induction Of Chronic Stress Reveals An Interplay Of Stress Granules And TDP-43 Pathological Aggregates In Human ALS Fibroblasts And iPSC-Neurons

Induction Of Chronic Stress Reveals An Interplay Of Stress Granules And TDP-43 Pathological Aggregates In Human ALS Fibroblasts And iPSC-Neurons

Conserved metabolite regulation of stress granule assembly via AdoMet

Biomolecular condensates in neurodegeneration and cancer

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