A new cellular model of pathological TDP-43: The neurotoxicity of stably expressed CTF25 of TDP-43 depends on the proteasome

Liu, Y.; Duan, Weisong; Guo, Yansu; Li, Z.; Han, Huihui; Zhang, S.; Yuan, Peng; Li, C.

doi:10.1016/j.neuroscience.2014.09.043

Cited by 29 publications

(18 citation statements)

References 36 publications

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“…3B). These bands represent the previously reported caspase cleaved C-terminal fragment that is considered to be the toxic component of TDP-43 aggregates (Liu et al 2014; Chiang et al 2016).…”

Section: Resultssupporting

confidence: 76%

Codon-optimized TDP-43-mediated neurodegeneration in a Drosophila model for ALS/FTLD

Yusuff

Chatterjee

Chang

et al. 2019

Preprint

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59Transactive response DNA binding protein-43 (TDP-43) is known to mediate neurodegeneration 60 associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The 61 exact mechanism by which TDP-43 exerts toxicity in the brains of affected patients remains unclear. In 62 a novel Drosophila melanogaster model, we report gain-of-function phenotypes due to misexpression of 63 insect codon-optimized version of human wild-type TDP-43 (CO-TDP-43) using both the binary 64 GAL4/UAS system and direct promoter fusion constructs. The CO-TDP-43 model showed robust tissue 65 specific phenotypes in the adult eye, wing, and bristles in the notum. Compared to non-codon optimized 66 transgenic flies, the CO-TDP-43 flies produced increased amount of high molecular weight protein, 67 exhibited pathogenic phenotypes, and showed cytoplasmic aggregation with both nuclear and 68 cytoplasmic expression of TDP-43. Further characterization of the adult retina showed a disruption in 69 the morphology and function of the photoreceptor neurons with the presence of acidic vacuoles that are 70 characteristic of autophagy. Based on our observations, we propose that TDP-43 has the propensity to 71 form toxic protein aggregates via a gain-of-function mechanism, and such toxic overload leads to 72 activation of protein degradation pathways such as autophagy. The novel codon optimized TDP-43 73model is an excellent resource that could be used in genetic screens to identify and better understand the 74 exact disease mechanism of TDP-43 proteinopathies and find potential therapeutic targets. 75 76 77 78 79 80 4 103 5 (Johnson et al.

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Section: Resultssupporting

confidence: 76%

Codon-optimized TDP-43-mediated neurodegeneration in a Drosophila model for ALS/FTLD

Yusuff

Chatterjee

Chang

et al. 2019

Preprint

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“…Furthermore, TDP-43 inclusions co-localize with markers of both autophagy and the proteasome, including p62/SQSTM1 (Brady et al, 2011). In the case of C-terminal TDP-43 fragments, the inhibition in degradation causes accumulation into large cytoplasmic inclusions, implying that decreased degradation potential in patients could be one mechanism leading to TDP-43 pathology in disease (Walker et al, 2013; Liu et al, 2014). Recently, detailed studies have revealed a critical difference in the clearance of soluble vs. insoluble TDP-43; soluble TDP-43 is primarily degraded via the proteasome whereas aggregated TDP-43 is primarily degraded via autophagy in cell culture (Scotter et al, 2014).…”

Section: Tdp-43mentioning

confidence: 99%

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

Shahheydari

Ragagnin

Walker

et al. 2017

Front. Mol. Neurosci.

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Protein homeostasis, or proteostasis, has an important regulatory role in cellular function. Protein quality control mechanisms, including protein folding and protein degradation processes, have a crucial function in post-mitotic neurons. Cellular protein quality control relies on multiple strategies, including molecular chaperones, autophagy, the ubiquitin proteasome system, endoplasmic reticulum (ER)-associated degradation (ERAD) and the formation of stress granules (SGs), to regulate proteostasis. Neurodegenerative diseases are characterized by the presence of misfolded protein aggregates, implying that protein quality control mechanisms are dysfunctional in these conditions. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that are now recognized to overlap clinically and pathologically, forming a continuous disease spectrum. In this review article, we detail the evidence for dysregulation of protein quality control mechanisms across the whole ALS-FTD continuum, by discussing the major proteins implicated in ALS and/or FTD. We also discuss possible ways in which protein quality mechanisms could be targeted therapeutically in these disorders and highlight promising protein quality control-based therapeutics for clinical trials.

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“…However, it may experience redistribution from nucleus to cytoplasm, form aggregates or inclusions in cytoplasm and lose its normal function in clinical observations 12 13 14 . A wealth of studies have revealed that mislocalization and aggregation of the C-terminal fragments of TDP-43 including TDP-35 (~35 kDa) and TDP-25 (~25 kDa) are critical for TDP-43 proteinopathies 5 15 16 , and especially the C-terminal GRR domain is of great importance for TDP-43 aggregation 17 18 19 20 . Some studies suggest that the Gln/Asn-rich domain in the C terminus is aggregation-prone 21 22 23 .…”

mentioning

confidence: 99%

Two mutations G335D and Q343R within the amyloidogenic core region of TDP-43 influence its aggregation and inclusion formation

Jiang

Zhao

Yin

et al. 2016

Sci Rep

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TDP-43 is a DNA/RNA binding protein associated with TDP-43 proteinopathies. Many mutations have been identified in the flexible C-terminal region, which is implicated in the disease pathology. We investigated four point mutations in the amyloidogenic core region (residues 311–360) of TDP-43 by biochemical and spectroscopic methods. We found that the G335D mutation enhances the aggregation and inclusion formation of TDP-43 and this mutant in TDP-35 (the C-terminal fragment of 35 kDa) exaggerates the antagonist effect on RNA processing by endogenous TDP-43; whereas Q343R gives an opposite effect. As a comparison, M337V and Q331K have very little impact on the aggregation and inclusion formation of TDP-43 or TDP-35. NMR structural analysis showed that the G335D mutant in the core region forms a loop linker between the two α-helices and promotes α-to-β transition, but Q343R loses the second helix and consequently the structural transformation. Thus, the propensity of structural transformation in the amyloidogenic core of TDP-43 determines its aggregation and inclusion formation. This study may provide a molecular mechanism of the TDP-43 proteinopathies caused by genetic mutations.

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A new cellular model of pathological TDP-43: The neurotoxicity of stably expressed CTF25 of TDP-43 depends on the proteasome

Cited by 29 publications

References 36 publications

Codon-optimized TDP-43-mediated neurodegeneration in a Drosophila model for ALS/FTLD

Codon-optimized TDP-43-mediated neurodegeneration in a Drosophila model for ALS/FTLD

Protein Quality Control and the Amyotrophic Lateral Sclerosis/Frontotemporal Dementia Continuum

Two mutations G335D and Q343R within the amyloidogenic core region of TDP-43 influence its aggregation and inclusion formation

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