The overexpression of TDP-43 in astrocytes causes neurodegeneration via a PTP1B-mediated inflammatory response

Lee, Shinrye; Kim, Seyeon; Kang, Ha‐Young; Lim, Hye Ryeong; Kwon, Younghwi; Jo, Myungjin; Jeon, Yu-Mi; Kim, Sang Ryong; Kim, Ki‐Young; Ha, Chang Man; Lee, Seongsoo; Kim, Hyungjun

doi:10.1186/s12974-020-01963-6

Cited by 44 publications

(51 citation statements)

References 85 publications

(100 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This indicates that the level of TDP-43 must be tightly regulated throughout life. GOF experiments also revealed that excess of TBPH or TDP-43 is highly toxic in muscles [ 270 , 306 , 307 ], glial cells [ 270 , 307 , 309 , 325 , 326 ], and in the eye [ 266 , 274 , 289 , 290 , 292 , 293 , 302 , 303 , 304 , 306 , 307 , 310 , 312 , 314 , 315 , 316 , 317 , 318 , 319 , 320 , 324 , 327 , 328 , 329 , 330 , 331 , 332 , 333 , 334 ]. Moreover, it was reported that TBPH or TDP-43 overexpression induces cell death, as was shown in motoneurons [ 266 , 289 , 290 , 301 ], glial cells [ 309 , 326 ], mushroom bodies [ 265 , 290 ], and in the eye.…”

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

“…This may explain some discrepancies between different GOF studies ( Table 9 and Table 10 ). Several phenotypes induced by TBPH /TDP-43 GOF, such as eye degeneration and climbing defects, show age-dependent progression [ 265 , 275 , 289 , 290 , 293 , 305 , 307 , 308 , 309 , 311 , 312 , 314 , 315 , 316 , 318 , 320 , 321 , 324 , 325 , 330 , 331 , 332 , 333 , 334 ]. As TBPH expression decreased with aging [ 338 ], one may speculate that reduced endogenous TBPH levels exacerbate GOF effects without excluding that phenotype aggravation may be due to continuous abnormal accumulation of TBPH /TDP-43.…”

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

“…Drosophila pan-glial TDP-43 increased the expression of the inflammatory genes Dorsal (the ortholog of human NF-kappa B,NF-κB and inducible Nitric Oxyde Synthase, iNOS) [ 325 ]. This was rescued by RNAi-induced glial knockdown of Ptp61F , the Drosophila ortholog of human Ptp1b encoding tyrosine phosphatase 1B, which is a ubiquitous enzyme anchored in the ER membrane, upregulated in neuroinflammatory conditions [ 355 ].…”

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

“…This was rescued by RNAi-induced glial knockdown of Ptp61F , the Drosophila ortholog of human Ptp1b encoding tyrosine phosphatase 1B, which is a ubiquitous enzyme anchored in the ER membrane, upregulated in neuroinflammatory conditions [ 355 ]. In addition, Ptp61F silencing mitigated the age-dependent climbing defects and the reduced lifespan induced by glial GOF of TDP-43 [ 325 ]. This study suggests that the Ptp1b -dependent inflammatory response may be associated with TDP-43 toxicity.…”

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

See 3 more Smart Citations

Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster

Layalle

They

Ourghani

et al. 2021

IJMS

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset neurodegenerative disease characterized by the progressive degeneration of upper and lower motoneurons. Most ALS cases are sporadic but approximately 10% of ALS cases are due to inherited mutations in identified genes. ALS-causing mutations were identified in over 30 genes with superoxide dismutase-1 (SOD1), chromosome 9 open reading frame 72 (C9orf72), fused in sarcoma (FUS), and TAR DNA-binding protein (TARDBP, encoding TDP-43) being the most frequent. In the last few decades, Drosophila melanogaster emerged as a versatile model for studying neurodegenerative diseases, including ALS. In this review, we describe the different Drosophila ALS models that have been successfully used to decipher the cellular and molecular pathways associated with SOD1, C9orf72, FUS, and TDP-43. The study of the known fruit fly orthologs of these ALS-related genes yielded significant insights into cellular mechanisms and physiological functions. Moreover, genetic screening in tissue-specific gain-of-function mutants that mimic ALS-associated phenotypes identified disease-modifying genes. Here, we propose a comprehensive review on the Drosophila research focused on four ALS-linked genes that has revealed novel pathogenic mechanisms and identified potential therapeutic targets for future therapy.

show abstract

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

Section: Tdp-43 Proteinopathy In the Fruit Flymentioning

confidence: 99%

See 2 more Smart Citations

Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster

Layalle

They

Ourghani

et al. 2021

IJMS

View full text Add to dashboard Cite

show abstract

“…To develop therapeutic interventions for neuroinflammatory and degenerative diseases, it is necessary to identify downstream signaling pathways of TDP-43 in reactive astrocytes. Lee et al recently revealed that TDP-43 overexpression in astrocytes causes neurodegeneration through a protein tyrosine phosphatase 1B (PTP1B)-mediated inflammatory response characterized by increased levels of inflammatory molecules, such as interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), lipocalin-2 (LCN2), and inducible nitric oxide synthase (iNOS) [ 22 ]. They also found that PTP1B regulates the inflammatory response via activation of the nuclear factor-κB (NF-κB) pathway, accompanied by increased phosphorylation of NF-κB subunit p65 in astrocytes.…”

Section: Introductionmentioning

confidence: 99%

Identification of Genetic Modifiers of TDP-43: Inflammatory Activation of Astrocytes for Neuroinflammation

Kim

Rahman

Park

et al. 2021

Cells

Self Cite

View full text Add to dashboard Cite

Transactive response DNA-binding protein 43 (TDP-43) is a ubiquitously expressed DNA/RNA-binding protein linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). TDP-43 has been implicated in numerous aspects of the mRNA life cycle, as well as in cell toxicity and neuroinflammation. In this study, we used the toxicity of the TDP-43 expression in Saccharomyces cerevisiae as an assay to identify TDP-43 genetic interactions. Specifically, we transformed human TDP-43 cDNAs of wild-type or disease-associated mutants (M337V and Q331K) en masse into 4653 homozygous diploid yeast deletion mutants and then used next-generation sequencing readouts of growth to identify yeast toxicity modifiers. Genetic interaction analysis provided a global view of TDP-43 pathways, some of which are known to be involved in cellular metabolic processes. Selected putative loci with the potential of genetic interactions with TDP-43 were assessed for associations with neurotoxicity and inflammatory activation of astrocytes. The pharmacological inhibition of succinate dehydrogenase flavoprotein subunit A (SDHA) and voltage-dependent anion-selective channel 3 (VDAC3) suppressed TDP-43-induced expression of proinflammatory cytokines in astrocytes, indicating the critical roles played by SDHA and VDAC3 in TDP-43 pathways during inflammatory activation of astrocytes and neuroinflammation. Thus, the findings of our TDP-43 genetic interaction screen provide a global landscape of TDP-43 pathways and may help improve our understanding of the roles of glia and neuroinflammation in ALS and FTD pathogenesis.

show abstract

Glial TDP‐43 and TDP‐43 induced glial pathology, focus on neurodegenerative proteinopathy syndromes

Prater

Latimer

Jayadev

2021

Glia

View full text Add to dashboard Cite

Since its discovery in 2006, TAR DNA binding protein 43 (TDP-43) has driven rapidly evolving research in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic predominant agerelated TDP-43 encephalopathy (LATE). TDP-43 mislocalization or aggregation is the hallmark of TDP-43 proteinopathy and is associated with cognitive impairment that can be mapped to its regional deposition. Studies in human tissue and model systems demonstrate that TDP-43 may potentiate other proteinopathies such as the amyloid or tau pathology seen in Alzheimer's Disease (AD) in the combination of AD+LATE.Despite this growing body of literature, there remain gaps in our understanding of whether there is heterogeneity in TDP-43 driven mechanisms across cell types.The growing observations of correlation between TDP-43 proteinopathy and glial pathology suggest a relationship between the two, including pathogenic glial cell-autonomous dysfunction and dysregulated glial immune responses to neuronal TDP-43. In this review, we discuss the available data on TDP-43 in glia within the context of the neurodegenerative diseases ALS and FTLD and highlight the current lack of information about glial TDP-43 interaction in AD+LATE. TDP-43 has proven to be a significant modulator of cognitive and neuropathological outcomes. A deeper understanding of its role in diverse cell types may provide relevant insights into neurodegenerative syndromes.

show abstract

The overexpression of TDP-43 in astrocytes causes neurodegeneration via a PTP1B-mediated inflammatory response

Cited by 44 publications

References 85 publications

Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster

Amyotrophic Lateral Sclerosis Genes in Drosophila melanogaster

Identification of Genetic Modifiers of TDP-43: Inflammatory Activation of Astrocytes for Neuroinflammation

Glial TDP‐43 and TDP‐43 induced glial pathology, focus on neurodegenerative proteinopathy syndromes

Contact Info

Product

Resources

About