The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

Liachko, Nicole F.; Saxton, Aleen; McMillan, Pamela J.; Strovas, Timothy J.; Currey, Heather N.; Taylor, Laura M.; Wheeler, Jeanna M.; Oblak, Adrian L.; Ghetti, Bernardino; Montine, Thomas J.; Keene, C. Dirk; Raskind, Murray A.; Bird, Thomas D.; Kraemer, Brian C.

doi:10.1007/s00401-016-1600-y

Cited by 42 publications

(47 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Calcineurin depletion in a C. elegans model of ALS increased phosphorylated TDP-43 and exacerbated motor deficits (Liachko et al, 2016). Furthermore, a yeast hybrid screen identified calcineurin as a binding partner of phosphorylated TDP-43 (S409/410), indicating that the phosphatase calcineurin functionally dephosphorylates pathological TDP-43 (Liachko et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, a yeast hybrid screen identified calcineurin as a binding partner of phosphorylated TDP-43 (S409/410), indicating that the phosphatase calcineurin functionally dephosphorylates pathological TDP-43 (Liachko et al, 2016). This work supports the increase in cytoplasmic phosphorylated TDP-43 observed in our model of hTDP-43 overexpression (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The phosphatase calcineurin regulates TDP-43 phosphorylation (Liachko et al, 2016). We further validated the interaction of TDP-43 and calcineurin and our data show that changes in expression of TDP-43 inversely regulate calcineurin expression.…”

Section: Discussionmentioning

confidence: 99%

“…Camk2a-tTA (tet-off, Jackson Lab 007004), TetO-hTDP-43 (developed by M. Gitcho and N. Cairns, Washington University School of Medicine, St. Louis, MO) and APPswe/PSEN1ΔE9 ( APP/PSEN1 ) (Jackson Lab, 005864) mice were maintained on a C57BL/6J background (Jackson Laboratory, stock # 000664) for this study) (Hodgkiss and Kelly, 1995; Liachko et al, 2016; Mulkey et al, 1994; Zeng et al, 2001). TetO-hTDP-43 mice were developed by PCR cloning of human TDP-43 cDNA into the pTRE-Tight response plasmid (Clontech Laboratories, 631059) containing a tetracycline-response element (tetO) and linearized for pronuclear injections at the Washington University Transgenic core facility.…”

Section: Methodsmentioning

confidence: 99%

“…Some studies have shown that TDP-43 proteinopathy may contribute to the cognitive impairment seen in AD (Josephs et al, 2014). Calcineurin is a Ca 2+ /calmodulin-dependent protein phosphatase known to regulate phosphorylation of TDP-43, long-term depression and depotentiation as well as synaptic plasticity and memory (Hodgkiss and Kelly, 1995; Liachko et al, 2016; Mulkey et al, 1994; Zeng et al, 2001). There is evidence that TDP-43 might be functionally involved in APP regulation and tau aggregation.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

TDP-43 expression influences amyloidβ plaque deposition and tau aggregation

Davis

Gan

Dowell

et al. 2017

Neurobiology of Disease

View full text Add to dashboard Cite

Although the main focus in Alzheimer’s disease (AD) has been an investigation of mechanisms causing Aβ plaque deposition and tau tangle formation, recent studies have shown that phosphorylated TDP-43 pathology is present in up to 50% of sporadic cases. Furthermore, elevated phosphorylated TDP-43 has been associated with more severe AD pathology. Therefore, we hypothesized that TDP-43 may regulate amyloid-beta precursor protein (APP) trafficking and tau phosphorylation/aggregation. In order to examine the role of TDP-43 in AD, we developed a transgenic mouse that overexpresses hippocampal and cortical neuronal TDP-43 in a mouse expressing familial mutations (K595N and M596L) in APP and presenilin 1 (PSEN1ΔE9). In our model, increased TDP-43 was related to increased tau aggregation as evidenced by thioflavin S-positive phosphorylated tau, which may implicate TDP-43 expression in pre-tangle formation. In addition, there was increased endosomal/lysosomal localization of APP and reduced Aβ plaque formation with increased TDP-43. Furthermore, there was decreased calcineurin with elevated TDP-43 expression. Since calcineurin is a phosphatase for TDP-43, the decreased calcineurin expression may be one mechanism leading to an increase in accumulation of diffuse phosphorylated TDP-43 in the hippocampus and cortex. We further show that when TDP-43 is knocked down there is an increase in calcineurin. In our model of selective TDP-43 overexpression in an APP/PSEN1 background, we show that TDP-43 decreases Aβ plaque deposition while increasing abnormal tau aggregation. These observations indicate that TDP-43 may play a role in regulating APP trafficking and tau aggregation. Our data suggest that TDP-43 could be a putative target for therapeutic intervention in AD affecting both Aβ plaque formation and tauopathy.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

TDP-43 expression influences amyloidβ plaque deposition and tau aggregation

Davis

Gan

Dowell

et al. 2017

Neurobiology of Disease

View full text Add to dashboard Cite

show abstract

Protein Phosphatase 1 dephosphorylates TDP‐43 and suppresses its function in tau exon 10 inclusion

Miao

Chen

et al. 2018

FEBS Letters

View full text Add to dashboard Cite

Transactive response DNA-binding protein of 43 kDa (TDP-43) regulates RNA processing, including alternative splicing of tau exon 10. Pathological TDP-43 is hyperphosphorylated. However, how do the protein phosphatase(s) (PP) regulate TDP-43 phosphorylation is unclear. Here, we found that both PP1 and PP2A were coimmunoprecipitated with TDP-43. Treatment with calyculin A, but not with okadaic acid, increased TDP-43 phosphorylation at Ser379, Ser403/404, and Ser409/410 in cultured cells. PP1α, PP1β, and PP1γ interacted with TDP-43. Overexpression of PP1α and PP1γ, but not PP1β, suppressed TDP-43 phosphorylation at Ser403/404 and Ser409/410 and TDP-43-induced tau exon 10 inclusion. These findings suggest that PP1α and PP1γ regulate TDP-43 phosphorylation and its function in tau exon 10 inclusion mainly through its phosphorylation at Ser403/404 and Ser409/410.

show abstract

Aberrant TDP‐43 phosphorylation: a key wind gap from TDP‐43 to TDP‐43 proteinopathy

Huang¹,

Huang

et al. 2021

Ibrain

View full text Add to dashboard Cite

TDP‐43 proteinopathy is a kind of neurodegenerative diseases related to the TAR DNA‐binding protein of 43‐kDa molecular weight (TDP‐43). The typical neurodegenerative diseases include amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), Parkinson's disease (PD) and so on. As the disease process cannot be blocked or slowed down, these patients have poor quality of life and poor prognosis, and bring a huge burden to the family and society. So far, the specific pathogenesis of TDP‐43 proteinopathy is not clear, and there is no effective preventive measure and treatment program for this kind of disease. TDP‐43 plays an important role in triggering or promoting the occurrence and progression of TDP‐43 proteinopathy. The hyperphosphorylation of TDP‐43 is undoubtedly an important factor in triggering or promoting the process of TDP‐43 proteinopathy. Hyperphosphorylation of TDP‐43 can inhibit the degradation of TDP‐43, aggravate the aggregation of TDP‐43 protein, increase the wrong localization of TDP‐43 in cells, and enhance the cytotoxicity of TDP‐43. More and more evidences show that the hyperphosphorylation of TDP‐43 plays an important role in the pathogenesis of TDP‐43 proteinopathy. Inhibition of TDP‐43 hyperphosphorylation may be one of the important strategies for the treatment of TDP‐43 proteinopathy. Therefore, this article reviews the role of TDP‐43 phosphorylation in TDP‐43 proteinopathy and the related mechanisms.

show abstract

The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

Cited by 42 publications

References 62 publications

TDP-43 expression influences amyloidβ plaque deposition and tau aggregation

TDP-43 expression influences amyloidβ plaque deposition and tau aggregation

Protein Phosphatase 1 dephosphorylates TDP‐43 and suppresses its function in tau exon 10 inclusion

Aberrant TDP‐43 phosphorylation: a key wind gap from TDP‐43 to TDP‐43 proteinopathy

Contact Info

Product

Resources

About