Mutant TDP-43 Causes Early-Stage Dose-Dependent Motor Neuron Degeneration in a TARDBP Knockin Mouse Model of ALS

Ebstein, Sarah Y.; Yagudayeva, Ilona; Shneider, Neil A.

doi:10.1016/j.celrep.2018.12.045

Cited by 76 publications

(71 citation statements)

References 34 publications

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“…The severity of TDP-43 toxicity is correlated with the levels of wild-type and mutant TDP-43 expression in the various cellular and animal models [17][18][19][20][21][22][23][24][25][26] . However, cytoplasmic TDP-43 aggregation is not always detectable in these models.…”

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confidence: 99%

Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons

2020

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Cytoplasmic aggregation of TDP-43 characterizes degenerating neurons in most cases of amyotrophic lateral sclerosis (ALS). Here, we develop an optogenetic TDP-43 variant (opTDP-43), whose multimerization status can be modulated in vivo through external light illumination. Using the translucent zebrafish neuromuscular system, we demonstrate that short-term light stimulation reversibly induces cytoplasmic opTDP-43 mislocalization, but not aggregation, in the spinal motor neuron, leading to an axon outgrowth defect associated with myofiber denervation. In contrast, opTDP-43 forms pathological aggregates in the cytoplasm after longer-term illumination and seeds non-optogenetic TDP-43 aggregation. Furthermore, we find that an ALS-linked mutation in the intrinsically disordered region (IDR) exacerbates the light-dependent opTDP-43 toxicity on locomotor behavior. Together, our results propose that IDR-mediated TDP-43 oligomerization triggers both acute and long-term pathologies of motor neurons, which may be relevant to the pathogenesis and progression of ALS.

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confidence: 99%

Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons

2020

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“…In striking contrast to heterozygous A315T (this study), Q331K [72], M337 V and G298S [24] knock-in mice, the heterozygous N390D/ + male mice develop molecular, cellular, and behavioral changes, with a spectrum of ALS-(See figure on previous page.) Fig.…”

Section: Resultsmentioning

confidence: 62%

“…Here we describe the use of knockin strategy to study ALS pathogenesis as a consequence of different ALS-associated TDP-43 mutations. A comparison of the pathologies of two heterozygous mouse models, N390D/+ and A315T/+ that we have generated to those knock-in mouse models reported in literature [24,26,72] demonstrate the distinctive pathological effects of different TDP-43 mutants. More importantly, the TDP-43(N390D/ +) mice appear to be a genuine ALS-TDP model for further basic and translational research of ALS-TDP.…”

Section: Resultsmentioning

confidence: 72%

“…However, mice with either one allele or both alleles mutated only exhibit subtle ALS-FTD-like phenotypes. More recently, Ebstein et al [24] have reported the generation of another two mouse models with knock-in of fALS-associated TDP-43 mutations, M337 V and G298S, that show relatively mild motor neuron degeneration in homozygous mice, but not in heterozygous ones, after the age of 2-year old. Here, we report the generation and characterization of two mouse models, each bearing a single ALS-TDP associated TDP-43 knockin mutation (N390D or A315T).…”

Section: Introductionmentioning

confidence: 99%

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A robust TDP-43 knock-in mouse model of ALS

Huang

Lee

et al. 2020

acta neuropathol commun

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Amyotrophic lateral sclerosis (ALS) is a fatal, adult-onset degenerative disorder of motor neurons. The diseased spinal cord motor neurons of more than 95% of amyotrophic lateral sclerosis (ALS) patients are characterized by the mis-metabolism of the RNA/DNA-binding protein TDP-43 (ALS-TDP), in particular, the presence of cytosolic aggregates of the protein. Most available mouse models for the basic or translational studies of ALS-TDP are based on transgenic overexpression of the TDP-43 protein. Here, we report the generation and characterization of mouse lines bearing homologous knock-in of fALS-associated mutation A315T and sALS-associated mutation N390D, respectively. Remarkably, the heterozygous TDP-43 (N390D/+) mice but not those heterozygous for the TDP-43 (A315T/+) mice develop a full spectrum of ALS-TDP-like pathologies at the molecular, cellular and behavioral levels. Comparative analysis of the mutant mice and spinal cord motor neurons (MN) derived from their embryonic stem (ES) cells demonstrates that different ALS-associated TDP-43 mutations possess critical ALS-causing capabilities and pathogenic pathways, likely modified by their genetic background and the environmental factors. Mechanistically, we identify aberrant RNA splicing of spinal cord Bcl-2 pre-mRNA and consequent increase of a negative regulator of autophagy, Bcl-2, which correlate with and are caused by a progressive increase of TDP-43, one of the early events associated with ALS-TDP pathogenesis, in the spinal cord of TDP-43 (N390D/+) mice and spinal cord MN derived from their ES cells. The TDP-43 (N390D/+) knock-in mice appear to be an ideal rodent model for basic as well as translational studies of ALS-TDP.

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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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Mutant TDP-43 Causes Early-Stage Dose-Dependent Motor Neuron Degeneration in a TARDBP Knockin Mouse Model of ALS

Cited by 76 publications

References 34 publications

Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons

Optogenetic modulation of TDP-43 oligomerization accelerates ALS-related pathologies in the spinal motor neurons

A robust TDP-43 knock-in mouse model of ALS

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

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