Single-copy expression of an amyotrophic lateral sclerosis-linked TDP-43 mutation (M337V) in BAC transgenic mice leads to altered stress granule dynamics and progressive motor dysfunction

Gordon, David F.; Dafinca, Ruxandra; Scaber, Jakub; Alegre-Abarrategui, Javier; Farrimond, Lucy; Scott, Connor; Biggs, David F.; Kent, Louisa; Oliver, Peter L.; Davies, Benjamin; Ansorge, Olaf; Wade‐Martins, Richard; Talbot, Kevin

doi:10.1016/j.nbd.2018.09.024

Cited by 75 publications

(95 citation statements)

References 67 publications

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“…Third, methionine--to--valine mutation of residues 336, 337 and 339 of the TDP43 LC domain yielded proteins that polymerize more rapidly than normal, and are partially resistant to H 2 O 2 --mediated inhibition of polymerization. We make note of the fact a M337V mutation has been observed in independent kindreds by human genetic studies of amyotrophic lateral sclerosis (Rutherford et al, 2008;Tamaoka et al, 2010), and that CRISPR--mediated introduction of this single amino acid change into the endogenous TDP43 gene of mice leads to profound neuropathology (Ebstein et al, 2019;Gordon et al, 2019). We hypothesize that methionine residues 336, 337 and 339 may be of particular importance to a "redox switch" evolutionarily crafted into the LC domain of TDP43.…”

Section: Discussionmentioning

confidence: 84%

Redox-mediated regulation of a labile, evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain

Lin

Zhou

Kato

et al. 2019

Preprint

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An evolutionarily conserved low complexity (LC) domain is found within a 152 residue segment localized to the carboxyl--terminal region of the TDP43 RNA--binding protein. This TDP43 LC domain contains ten conserved methionine residues. Self--association of this domain leads to the formation of liquid--like droplets composed of labile, cross--β polymers. Exposure of polymers to low concentrations of H 2 O 2 leads to a phenomenon of droplet melting that can be reversed upon exposure of the oxidized protein to the MsrA and MsrB methionine sulfoxide reductase enzymes, thioredoxin, thioredoxin reductase and NADPH. Morphological features of the cross--β polymers were revealed by a method of H 2 O 2 --mediated footprinting. Similar TDP43 LC domain footprints were observed in highly polymerized, hydrogel samples, liquid--like droplet samples, and living cells. The ability of H 2 O 2 to impede cross--β polymerization was abrogated by a prominent ALS--causing mutation that changes methionine residue 337 to valine. These observations offer potentially useful insight into the biological role of TDP43 in facilitating synapse--localized translation, as well as aberrant aggregation of the protein in neurodegenerative disease.

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Section: Discussionmentioning

confidence: 84%

Redox-mediated regulation of a labile, evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain

Lin

Zhou

Kato

et al. 2019

Preprint

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“…B6;129S6-Gt(ROSA)26Sor m1(TARDBP*M337V/Ypet)Tlbt /J (WT and M337V TDP43, Jackson Laboratory strain #029266, https://www.jax.org/strain/029266) and B6N;B6J-Fustm1Emcf/H (Fus +/+ and Fus Δ14/+ ) mice were maintained on a C57BL/6 background and genotyped as detailed previously (Devoy et al 2018;Gordon et al 2018). ChAT-eGFP mice used for motor versus sensory analyses were 79-134 days old.…”

Section: Animalsmentioning

confidence: 99%

“…Recently reported transgenic TDP-43 M337V mice display an impairment in motor function and neuromuscular junction abnormalities beginning at 9 months in homozygous mutants without motor neuron loss up to 12 months (Gordon et al 2018). We therefore first assessed retrograde transport of signalling endosomes at 9 months of age in heterozygous and homozygous TDP-43 M337V and TDP-43 WT mice and non-transgenic (NTg) controls (Fig.…”

Section: In Vivo Axonal Transport Is Pre-symptomatically Impaired In mentioning

confidence: 99%

“…2C and D). Mutant TDP-43 mice do not show clear behavioural phenotypes at 3 months (Gordon et al 2018); we therefore assessed transport at this early time point to see whether axonal transport defects precede symptom onset and thus may contribute to motor neuron pathology. Indeed, a similar deficiency in mutant TDP-43 transport was observed at 3 months, while TDP-43 WT transport remained unperturbed (Fig.…”

Section: In Vivo Axonal Transport Is Pre-symptomatically Impaired In mentioning

confidence: 99%

“…We have thus performed pseudolongitudinal assessments of in vivo axonal transport in two recently engineered mouse models of ALS with mutations in genes encoding DNA/RNA-binding proteins instrumental to RNA processing, TDP-43 (Gordon et al 2018) and Fus (Devoy et al 2018). Transgenic TDP-43 M337V and humanised, knock-in Fus Δ14/+ mice, which both express mutant protein at physiologically-relevant levels, have been used to assess signalling endosome trafficking along peripheral nerve axons to address the importance of altered axonal transport to ALS neuropathology.…”

Section: Introductionmentioning

confidence: 99%

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ALS mice carrying pathological mutant TDP-43, but not mutant FUS, display axonal transport defects in vivo

Sleigh

Tosolini

Gordon

et al. 2018

Preprint

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Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease resulting from a complex interplay between genetics and environment. Impairments in the basic neuronal process of axonal transport have been identified in several ALS models. However, in vivo evidence of early/pre-symptomatic deficiencies in neuronal cargo trafficking remains limited, thus the pathogenic importance of axonal transport to the ALS disease spectrum remains to be fully resolved. We therefore analysed the in vivo dynamics of retrogradely transported, neurotrophin-containing signalling endosomes in motor neuron axons of two new mouse models of ALS that have mutations in different RNA processing genes (Tardbp and Fus). TDP-43 M337V mice, which show neuromuscular pathology but no overt motor neuron loss, displayed in vivo perturbations in axonal transport that manifested between 1.5 and 3 months and preceded motor symptom onset. In contrast, signalling endosome transport remained largely unaffected in mutant Fus Δ14/+ mice, despite 20% motor neuron loss. These findings indicate that deficiencies in retrograde neurotrophin signalling and axonal transport are not common to all ALS-linked genes, and that there are inherent and mechanistic distinctions in the pathogenesis of ALS caused by mutations in different RNA processing genes.

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Influence of ALS‐linked M337V mutation on the conformational ensembles of TDP‐43_321–340 peptide monomer and dimer

et al. 2023

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The transactive response (TAR) DNA/RNA‐binding protein 43 (TDP‐43) can self‐assemble into both functional stress granules via liquid–liquid phase separation (LLPS) and pathogenic amyloid fibrillary aggregates that are closely linked to amyotrophic lateral sclerosis. Previous experimental studies reported that the low complexity domain (LCD) of TDP‐43 plays an essential role in the LLPS and aggregation of the full‐length protein, and it alone can also undergo LLPS to form liquid droplets mainly via intermolecular interactions in the 321–340 region. And the ALS‐associated M337V mutation impairs LCD's LLPS and facilitates liquid–solid phase transition. However, the underlying atomistic mechanism is not well understood. Herein, as a first step to understand the M337V‐caused LLPS disruption of TDP‐43 LCD mediated by the 321–340 region and the fibrillization enhancement, we investigated the conformational properties of monomer/dimer of TDP‐43321–340 peptide and its M337V mutant by performing extensive all‐atom explicit‐solvent replica exchange molecular dynamic simulations. Our simulations demonstrate that M337V mutation alters the residue regions with high helix/β‐structure propensities and thus affects the conformational ensembles of both monomer and dimer. M337V mutation inhibits helix formation in the N‐terminal Ala‐rich region and the C‐terminal mutation site region, while facilitating their long β‐sheet formation, albeit with a minor impact on the average probability of both helix structure and β‐structure. Further analysis of dimer system shows that M337V mutation disrupts inter‐molecular helix–helix interactions and W334‐W334 π‐π stacking interactions which were reported to be important for the LLPS of TDP‐43 LCD, whereas enhances the overall peptide residue‐residue interactions and weakens peptide‐water interactions, which is conducive to peptide fibrillization. This study provides mechanistic insights into the M337V‐mutation‐induced impairment of phase separation and facilitation of fibril formation of TDP‐43 LCD.

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Single-copy expression of an amyotrophic lateral sclerosis-linked TDP-43 mutation (M337V) in BAC transgenic mice leads to altered stress granule dynamics and progressive motor dysfunction

Abstract: Single-copy expression of an amyotrophic lateral sclerosis-linked TDP-43 mutation (M337V) in BAC transgenic mice leads to altered stress granule dynamics and progressive motor dysfunction. Ynbdi (2018),

Cited by 75 publications

References 67 publications

Redox-mediated regulation of a labile, evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain

Redox-mediated regulation of a labile, evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain

ALS mice carrying pathological mutant TDP-43, but not mutant FUS, display axonal transport defects in vivo

Influence of ALS‐linked M337V mutation on the conformational ensembles of TDP‐43_321–340 peptide monomer and dimer

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Single-copy expression of an amyotrophic lateral sclerosis-linked TDP-43 mutation (M337V) in BAC transgenic mice leads to altered stress granule dynamics and progressive motor dysfunction

Abstract: Single-copy expression of an amyotrophic lateral sclerosis-linked TDP-43 mutation (M337V) in BAC transgenic mice leads to altered stress granule dynamics and progressive motor dysfunction. Ynbdi (2018),

Cited by 75 publications

References 67 publications

Redox-mediated regulation of a labile, evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain

Redox-mediated regulation of a labile, evolutionarily conserved cross-β structure formed by the TDP43 low complexity domain

ALS mice carrying pathological mutant TDP-43, but not mutant FUS, display axonal transport defects in vivo

Influence of ALS‐linked M337V mutation on the conformational ensembles of TDP‐43321–340 peptide monomer and dimer

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Influence of ALS‐linked M337V mutation on the conformational ensembles of TDP‐43_321–340 peptide monomer and dimer