4-Hydroxynonenal induces persistent insolubilization of TDP-43 and alters its intracellular localization

Kabuta, Chihana; Kono, Kanako; Wada, Keiji; Kabuta, Tomohiro

doi:10.1016/j.bbrc.2015.05.027

Cited by 22 publications

(16 citation statements)

References 32 publications

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“…2E). We also observed phosphorylated TDP-43 in APP/PS1 mice, which is likely due in part to stress causing cytoplasmic TDP-43 localization as seen in a tau mouse model (Ayala et al, 2011a; Clippinger et al, 2013; Herman et al, 2011; Kabuta et al, 2015; Moujalled et al, 2013). (Fig.…”

Section: Resultssupporting

confidence: 56%

TDP-43 expression influences amyloidβ plaque deposition and tau aggregation

Davis

Gan

Dowell

et al. 2017

Neurobiology of Disease

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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.

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Section: Resultssupporting

confidence: 56%

TDP-43 expression influences amyloidβ plaque deposition and tau aggregation

Davis

Gan

Dowell

et al. 2017

Neurobiology of Disease

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“…Several stressors, such as oxidative, osmotic, heat shock, and ER stress were able to recapitulate the cytoplasmic redistribution and stress granule association of TDP-43 (Colombrita et al 2009;Liu-Yesucevitz et al 2010;Dewey et al 2011;McDonald et al 2011;Leggett et al 2012). Importantly, some of these stressinduced granules turned into insoluble aggregates and were shown to persist after removal of the stressor (Dewey et al 2011;Cohen et al 2015;Feiler et al 2015;Kabuta et al 2015). Importantly, recent elegant biophysical studies (Burke et al 2015;Molliex et al 2015;Patel et al 2015) support the hypothesis that soluble and dynamic stress granules can transform into insoluble and irreversible aggregates in vitro.…”

Section: Increase In Local Concentration and Rna Association In Stresmentioning

confidence: 74%

Prion‐like propagation as a pathogenic principle in frontotemporal dementia

Hock

Polymenidou

2016

Journal of Neurochemistry

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Frontotemporal dementia is a devastating neurodegenerative disease causing stark alterations in personality and language. Characterized by severe atrophy of the frontal and temporal brain lobes, frontotemporal dementia (FTD) shows extreme heterogeneity in clinical presentation, genetic causes, and pathological findings. Like most neurodegenerative diseases, the initial symptoms of FTD are subtle, but increase in severity over time, as the disease progresses. Clinical progression is paralleled by exacerbation of pathological findings and the involvement of broader brain regions, which currently lack mechanistic explanation. Yet, a flurry of studies indicate that protein aggregates accumulating in neurodegenerative diseases can act as propagating entities, amplifying their pathogenic conformation, in a way similar to infectious prions. In this prion-centric view, FTD can be divided into three subtypes, TDP-43 or FUS proteinopathy and tauopathy. Here, we review the current evidence that FTD-linked pathology propagates in a prion-like manner and discuss the implications of these findings for disease progression and heterogeneity.

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“…2a-e), consistent with a conserved role for calcineurin as a TDP-43 phosphatase. We and others have observed a link between total TDP-43 and pTDP levels; when pTDP is increased, total TDP-43 protein also increases [7, 26, 33, 62]. This may be due to changes in protein stability or pTDP’s blockade of normal TDP-43 protein degradation pathways.…”

Section: Resultsmentioning

confidence: 90%

“…pTDP may influence aspects of TDP-43 protein metabolism or function, possibly in response to specific or general cellular stresses. While the endogenous or environmental triggers of neuronal TDP-43 phosphorylation remain unclear, in mammalian cell culture full-length pTDP is induced under conditions of oxidative stress [21, 26]. If cellular homeostasis is disrupted, an imbalance between phosphate addition and removal on TDP-43 could lead to accumulation of pTDP and subsequent neurotoxicity (Fig.…”

Section: Discussionmentioning

confidence: 99%

The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

et al. 2016

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Detergent insoluble inclusions of TDP-43 protein are hallmarks of the neuropathology in over 90% of amyotrophic lateral sclerosis (ALS) cases and approximately half of frontotemporal dementia (FTLD-TDP) cases. In TDP-43 proteinopathy disorders, lesions containing aggregated TDP-43 protein are extensively post-translationally modified, with phosphorylated TDP-43 (pTDP) being the most consistent and robust marker of pathological TDP-43 deposition. Abnormally phosphorylated TDP-43 has been hypothesized to mediate TDP-43 toxicity in many neurodegenerative disease models. To date several different kinases have been implicated in the genesis of pTDP, but no phosphatases have been shown to reverse pathological TDP-43 phosphorylation. We have identified the phosphatase calcineurin as an enzyme binding to and catalyzing the removal of pathological C-terminal phosphorylation of TDP-43 in vitro. In C. elegans models of TDP-43 proteinopathy, genetic elimination of calcineurin results in accumulation of excess pTDP, exacerbated motor dysfunction, and accelerated neurodegenerative changes. In cultured human cells, treatment with FK506 (tacrolimus), a calcineurin inhibitor, results in accumulation of pTDP species. Lastly, calcineurin co-localizes with pTDP in degenerating areas of the central nervous system in subjects with FTLD-TDP and ALS. Taken together these findings suggest calcineurin acts on pTDP as a phosphatase in neurons. Furthermore, patient treatment with calcineurin inhibitors may have unappreciated adverse neuropathological consequences.

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4-Hydroxynonenal induces persistent insolubilization of TDP-43 and alters its intracellular localization

Cited by 22 publications

References 32 publications

TDP-43 expression influences amyloidβ plaque deposition and tau aggregation

TDP-43 expression influences amyloidβ plaque deposition and tau aggregation

Prion‐like propagation as a pathogenic principle in frontotemporal dementia

The phosphatase calcineurin regulates pathological TDP-43 phosphorylation

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