Knockdown of phosphotyrosyl phosphatase activator induces apoptosis via mitochondrial pathway and the attenuation by simultaneous tau hyperphosphorylation

Luo, Danju; Feng, Qiong; Wang, Zhi-Hao; Sun, Dongsheng; Wang, Qun; Wang, Jian‐Zhi; Liu, Gong‐Ping

doi:10.1111/jnc.12761

Cited by 26 publications

(19 citation statements)

References 46 publications

(76 reference statements)

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“…Protein phosphatases play major roles in the cell including metabolism, cell division, and growth. Knockdown of phosphotyrosyl phosphatase activator (PTPA) was observed in Alzheimer’s disease to induce apoptosis [ 68 ]. Hyperphosphorylated tau protein aggregates also characterize AD.…”

Section: The Genetics Of Neurodegenerative Diseasesmentioning

confidence: 99%

Mitochondrial Biology and Neurological Diseases

Arun¹,

Liu²,

Dönmez

2016

103

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Mitochondria are extremely active organelles that perform a variety of roles in the cell including energy production, regulation of calcium homeostasis, apoptosis, and population maintenance through fission and fusion. Mitochondrial dysfunction in the form of oxidative stress and mutations can contribute to the pathogenesis of various neurodegenerative diseases such as Parkinson’s (PD), Alzheimer’s (AD), and Huntington’s diseases (HD). Abnormalities of Complex I function in the electron transport chain have been implicated in some neurodegenerative diseases, inhibiting ATP production and generating reactive oxygen species that can cause major damage to mitochondriaMutations in both nuclear and mitochondrial DNA can contribute to neurodegenerative disease, although the pathogenesis of these conditions tends to focus on nuclear mutations. In PD, nuclear genome mutations in the PINK1 and parkin genes have been implicated in neurodegeneration [1], while mutations in APP, PSEN1 and PSEN2 have been implicated in a variety of clinical symptoms of AD [5]. Mutant htt protein is known to cause HD [2]. Much progress has been made to determine some causes of these neurodegenerative diseases, though permanent treatments have yet to be developed. In this review, we discuss the roles of mitochondrial dysfunction in the pathogenesis of these diseases.

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Section: The Genetics Of Neurodegenerative Diseasesmentioning

confidence: 99%

Mitochondrial Biology and Neurological Diseases

Arun¹,

Liu²,

Dönmez

2016

103

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“…Tau hyperphosphorylation dissociates microtubules and thus disrupts axonal transport [14- 81 18]. Recent studies suggest that tau phosphorylation is actively involved in regulating cell 82 viability [19][20][21]. Normally, tau is largely located in the neuronal axons [22].…”

Section: Introductionmentioning

confidence: 99%

Tau accumulation activates STAT1 triggering memory deficits via suppressing NMDA receptor expression

Hong

Wang

et al. 2018

Preprint

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Intracellular tau accumulation forming neurofibrillary tangles is hallmark pathology of Alzheimer's disease (AD), but how tau accumulation induces synapse impairment is elusive. By overexpressing human full-length wildtype tau (termed hTau) to mimic tau abnormality as seen in the brain of sporadic AD patients, we found that hTau accumulation activated JAK2 to phosphorylate STAT1 (Signal Transducer and Activator of Transcription 1) at Tyr701 leading to STAT1 dimerization, nuclear translocation and its activation. STAT1 activation suppressed expression of N-methyl-D-aspartate receptors (NMDARs) through direct binding to the specific GAS element of GluN1, GluN2A and GluN2B promoters, while knockdown STAT1 by AAV-Cre in STAT1flox/flox mice or expressing dominant negative Y701F-STAT1 efficiently rescued hTau-induced suppression of NMDARs expression with amelioration of synaptic functions and memory performance. These findings indicate that hTau accumulation impairs synaptic plasticity through JAK2/STAT1-induced suppression of NMDARs expression, revealing a novel mechanism for hTau-associated synapse and memory deficits.

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“…As tau experiences phosphorylation, aggregation and deposition during the course of AD development and progression, it will lose its ability to maintain the stability of microtubes (70). Moreover, the aggregated form of tau will induce neurotoxicity (39), leading to the apoptosis of neurons (71). Long-term potentiation (LTP) was obviously suppressed in tau P301S Tg mice, which potentially affected the memory of the mice (72).…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin A1 inhibits the phosphorylation of tau via activating protein phosphotase 2A in a michael addition mechanism at the site of cysteine 377

Guan

Wang

2020

Preprint

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Background: Prostaglandin (PG) A1 is a metabolic product of cyclooxygenase 2 (COX-2), which potentially involved in regulating the development and progression of Alzheimer’s disease (AD). As a cyclopentenone (cy) PG, PGA1 is characterized by the presence of a chemically reactive α, β-unsaturated carbonyl. Although PGA1 is potentially involved in regulating multiple biological processes via michael addition, its specific roles in AD remained unclear.Methods: The tauP301S transgenic (Tg) mice were employed as in vivo AD models and neuroblastoma (N) 2a cells as in vitro neuronal models. By intracerebroventricular injected (i.c.v) with PGA1, the binding proteins to PGA1 are analyzed by HPLC-MS-MS. In addition, western blots are used to determine the phosphorylation of tau in PGA1 treated Tg mice in the absence or presence of okadaic acid (OA), an inhibitor of protein phosphotase (PP) 2A. Combining a synthesis of pull down assay, immunoprecipitation, western blots and HPLC-MS-MS, PP2A scaffold subunit A alpha (PPP2R1A) was identified to be activated by directly binding on PGA1 in cysteine 377-dependent manner. Via inhibiting the hyperphosphorylation of tau, morris maze test was employed to determine the inhibitory effects of PGA1 on cognitive decline of tauP301S Tg mice.Results: By incubation with neuroblastoma (n)2a cells and pull down assay, mass spectra (MS) analysis revealed that PGA1 binds with more than 1000 proteins, among which contains the proteins of AD, especially tau protein. Moreover, short-term administration of PGA1 to tauP301S Tg mice significantly decreased the phosphorylation of tau at the sites of Thr181, Ser202 and Ser404 in a dose-dependent manner. To the reason, it’s caused by activating PPP2R1A in tauP301S Tg mice. More importantly, PGA1 has the ability to form michael adduct with PPP2R1A via its cysteine 377 motif, which is critical for the enzymatic activity of PP2A. By activating PP2A, long-term application of PGA1 to tauP301S Tg mice significantly reduced the phosphorylation of tau, which results in improving the cognitive decline of tauP301S Tg mice.Conclusion: Our data provided the first insights needed to decipher the mechanisms underlying the ameliorating effects of PGA1 on cognitive decline of tauP301S Tg mice via activating PP2A in a PPP2R1AC377-dependent Michael adducting mechanisms.

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Knockdown of phosphotyrosyl phosphatase activator induces apoptosis via mitochondrial pathway and the attenuation by simultaneous tau hyperphosphorylation

Cited by 26 publications

References 46 publications

Mitochondrial Biology and Neurological Diseases

Mitochondrial Biology and Neurological Diseases

Tau accumulation activates STAT1 triggering memory deficits via suppressing NMDA receptor expression

Prostaglandin A1 inhibits the phosphorylation of tau via activating protein phosphotase 2A in a michael addition mechanism at the site of cysteine 377

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