Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis

Ditsworth, Dara; Maldonado, Marcus; McAlonis-Downes, Melissa; Sun, Shuying; Seelman, Amanda; Drenner, Kevin; Arnold, Eveline S.; Ling, Shuo-Chien; Pizzo, Donald; Ravits, John; Cleveland, Don W.; Cruz, Sandrine Da

doi:10.1007/s00401-017-1698-6

Cited by 63 publications

(56 citation statements)

References 74 publications

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“…A likely, disease-related stress is the reduction in nuclear import during normal aging (D'Angelo et al, 2009;Mertens et al, 2015;Scaffidi and Misteli, 2006), coupled with further import inhibition in different neurodegenerative diseases (Freibaum et al, 2015;Gasset-Rosa et al, 2017), including ALS (Boeynaems et al, 2016;Ditsworth et al, 2017;Freibaum et al, 2015;Jovi ci c et al, 2015;Zhang et al, 2015Zhang et al, , 2018. Here we demonstrate that major regulators of nucleocytoplasmic trafficking (RanGap1, Ran, Nup107, and Nup62) are abnormally localized as a consequence of induced cytoplasmic LLPS of TDP-43.…”

Section: Discussionmentioning

confidence: 99%

“…Recognizing that defects in nuclear membrane structure and/or nucleocytoplasmic transport have been reported in the nervous systems of patients with ALS caused by hexanucleotide repeat expansion in C9orf72 (Freibaum et al, 2015;Jovi ci c et al, 2015;Zhang et al, 2015) or mutation in SOD1 (Kinoshita et al, 2009) and in mouse models of TDP-43 or SOD1 mutant-mediated disease (Chou et al, 2018;Ditsworth et al, 2017;Zhang et al, 2006), we examined the integrity of the nuclear membrane and nuclear import in non-cycling SH-SY5Y neuronal cells with cytoplasmic LLPS of TDP-43. Transient exposure to amyloidlike particles provoked gradual retention in the cytoplasm of components critical for nucleocytoplasmic transport ( Figures 8A-8D).…”

Section: Disrupted Nucleocytoplasmic Transport Enhances Nuclear Deplementioning

confidence: 99%

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Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death

Gasset-Rosa

et al. 2019

Neuron

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Graphical Abstract Highlights d Transient stress induces long-lasting phase separation of cytoplasmic TDP-43 d Formation/maintenance of phase separated TDP-43 is independent of stress granules d Phase-separated TDP-43 inhibits nuclear transport by demixing importin-a and Nup62 d Cytoplasmic TDP-43 de-mixing depletes nuclear TDP-43 and induces cell death Authors SUMMARY While cytoplasmic aggregation of TDP-43 is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia, how aggregates form and what drives its nuclear clearance have not been determined.Here we show that TDP-43 at its endogenous level undergoes liquid-liquid phase separation (LLPS) within nuclei in multiple cell types. Increased concentration of TDP-43 in the cytoplasm or transient exposure to sonicated amyloid-like fibrils is shown to provoke long-lived liquid droplets of cytosolic TDP-43 whose assembly and maintenance are independent of conventional stress granules. Cytosolic liquid droplets of TDP-43 accumulate phosphorylated TDP-43 and rapidly convert into gels/ solids in response to transient, arsenite-mediated stress. Cytoplasmic TDP-43 droplets slowly recruit importin-a and Nup62 and induce mislocalization of RanGap1, Ran, and Nup107, thereby provoking inhibition of nucleocytoplasmic transport, clearance of nuclear TDP-43, and cell death. These findings identify a neuronal cell death mechanism that can be initiated by transient-stress-induced cytosolic demixing of TDP-43.

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Section: Discussionmentioning

confidence: 99%

Section: Disrupted Nucleocytoplasmic Transport Enhances Nuclear Deplementioning

confidence: 99%

Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death

Gasset-Rosa

et al. 2019

Neuron

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383

418

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“…The availability of appropriate ALS mouse models is essential for understanding ALS disease mechanisms and the development of therapeutic drugs. Most of previously developed ALS-TDP mouse models are based on a transgenic approach, whereby wild type or mutant TDP-43 is expressed under the control of different promoters [18,23,40,63]. This approach is limited by the cell type specificity of the promoters used to express the wild type and mutant TDP-43 transgenes, so the timing and level of the transgene expression is difficult to control.…”

Section: Resultsmentioning

confidence: 99%

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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“…Astrocytes differentiated from human induced pluripotent stem cells (iPSCs) carrying an ALS-linked mutant TDP-43 show subcellular mislocalization of TDP-43 and decreased cell survival [46]. In addition, reduction of mutant TDP-43 selectively in motor neurons does not attenuate astrogliosis, suggesting that astrocyte pathology may be an important component in models of TDP-43 proteinopathy [47]. Motor neuron degeneration in FUS and c9orf72 models is also associated with marked astrocytosis [48–51].…”

Section: Astrogliosis In Alsmentioning

confidence: 99%

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

Pehar

Harlan

Killoy

et al. 2018

CPD

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Amyotrophic lateral sclerosis (ALS) is characterized by the progressive degeneration of motor neurons in the spinal cord, brain stem, and motor cortex. The molecular mechanism underlying the progressive degeneration of motor neuron remains uncertain but involves a non-cell autonomous process. In acute injury or degenerative diseases astrocytes adopt a reactive phenotype known as astrogliosis. Astrogliosis is a complex remodeling of astrocyte biology and most likely represents a continuum of potential phenotypes that affect neuronal function and survival in an injury-specific manner. In ALS patients, reactive astrocytes surround both upper and lower degenerating motor neurons and play a key role in the pathology. It has become clear that astrocytes play a major role in ALS pathology. Through loss of normal function or acquired new characteristics, astrocytes are able to influence motor neuron fate and the progression of the disease. The use of different cell culture models indicates that ALS-astrocytes are able to induce motor neuron death by secreting a soluble factor(s). Here, we discuss several pathogenic mechanisms that have been proposed to explain astrocyte-mediated motor neuron death in ALS. In addition, examples of strategies that revert astrocyte-mediated motor neuron toxicity are reviewed to illustrate the therapeutic potential of astrocytes in ALS. Due to the central role played by astrocytes in ALS pathology, therapies aimed at modulating astrocyte biology may contribute to the development of integral therapeutic approaches to halt ALS progression.

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Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis

Cited by 63 publications

References 74 publications

Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death

Cytoplasmic TDP-43 De-mixing Independent of Stress Granules Drives Inhibition of Nuclear Import, Loss of Nuclear TDP-43, and Cell Death

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

Role and Therapeutic Potential of Astrocytes in Amyotrophic Lateral Sclerosis

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