Activation of Asparaginyl Endopeptidase Leads to Tau Hyperphosphorylation in Alzheimer Disease

Basurto-Islas, Gustavo; Grundke‐Iqbal, Inge; Tung, Yunn Chyn; Liu, Fei; Iqbal, Khalid

doi:10.1074/jbc.m112.446070

Cited by 112 publications

(119 citation statements)

References 58 publications

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“…We showed that VDAC1 is cleaved by AEP (EC 3.4.22.34), a cysteine protease mainly located in endolysosomes. AEP plays important roles in regulation of the immune system (45) and in cancer (46,47) and has recently been shown to cleave the protein tau in Alzheimer's disease (48,49). In addition, its expression and activity are regulated by TP53 (50), and it cleaves peptide bonds carboxy terminal to asparagine (51).…”

Section: Discussionmentioning

confidence: 99%

Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia

Brahimi-Horn

Lacas‐Gervais

Adaixo

et al. 2015

Molecular and Cellular Biology

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The oxygen-limiting (hypoxic) microenvironment of tumors induces metabolic reprogramming and cell survival, but the underlying mechanisms involving mitochondria remain poorly understood. We previously demonstrated that hypoxia-inducible factor 1 mediates the hyperfusion of mitochondria by inducing Bcl-2/adenovirus E1B 19-kDa interacting protein 3 and posttranslational truncation of the mitochondrial ATP transporter outer membrane voltage-dependent anion channel 1 in hypoxic cells. In addition, we showed that truncation is associated with increased resistance to drug-induced apoptosis and is indicative of increased patient chemoresistance. We now show that silencing of the tumor suppressor TP53 decreases truncation and increases drug-induced apoptosis. We also show that TP53 regulates truncation through induction of the mitochondrial protein Mieap. While we found that truncation was independent of mitophagy, we observed local microfusion between mitochondria and endolysosomes in hypoxic cells in culture and in patients' tumor tissues. Since we found that the endolysosomal asparagine endopeptidase was responsible for truncation, we propose that it is a readout of mitochondrial-endolysosomal microfusion in hypoxia. These novel findings provide the framework for a better understanding of hypoxic cell metabolism and cell survival through mitochondrial-endolysosomal microfusion regulated by hypoxia-inducible factor 1 and TP53. Hypoxia is a natural occurring stress that results in compensatory changes in metabolism and cell survival during embryonic development and tumor growth. Hypoxia stabilizes and activates the transcription factor hypoxia-inducible factor (HIF) through inhibition of oxygen-dependent hydroxylases that earmark the alpha subunit of HIF for proteasomal degradation (1). HIF induces or represses the expression of genes implicated in a myriad of functions, including those regulating metabolism and resistance to drug-induced cell death. Genes coding for the enzymes of the glycolytic pathway, including hexokinase, are highly induced by HIF-1, and this is in part responsible for the switch in metabolism from mitochondrial respiration to glycolysis in cancer cells. Considerable studies have pointed to the Warburg effect, also termed aerobic glycolysis, as the major adaptive response of cancer cells, but mitochondrial metabolism and mitochondrial dynamics are also starting to be recognized as important adaptive strategies of cancer cells (2). Mitochondria are critical organelles that regulate both metabolism and cell death. They are dynamic organelles that continuously undergo fission and fusion during cell growth (3, 4). Under stress conditions, such as nutrient depletion or hypoxia, mitochondria either fragment or are degraded by HIF-dependent mitophagy (mitochondrial removal by autophagy) (5) or hyperfuse together to form elongated or rounded structures that optimize ATP production and promote cell survival (6-11).We reported previously that certain cell lines exposed to hypoxia contained enlarged mitochon...

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Section: Discussionmentioning

confidence: 99%

Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia

Brahimi-Horn

Lacas‐Gervais

Adaixo

et al. 2015

Molecular and Cellular Biology

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“…This molecular mechanism (Fig. 7) is different from that involving cerebral ischemia and hypoxia, which inhibit PP2A by the activation of asparaginyl endopeptidase and the consequent cleavage and translocation of I 2 PP2A in AD and ALS (6,19,21,30).…”

Section: Discussionmentioning

confidence: 99%

“…(19) and demethylation of its catalytic subunit, PP2Ac (20). To examine whether PP2A inactivation is involved in abnormal hyperphosphorylation of tau in PD cases, we assayed the PP2A activity in autopsied brains from patients with Guam PD and age-matched controls from Guam by phosphatase ELISA (21). We found a significant (P < 0.05) decrease in PP2A activity in PD compared with nonneurological controls from Guam (Fig.…”

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confidence: 99%

Tau pathology involves protein phosphatase 2A in Parkinsonism-dementia of Guam

Arif

Kazim

Grundke‐Iqbal

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Parkinsonism-dementia (PD) of Guam is a neurodegenerative disease with parkinsonism and early-onset Alzheimer-like dementia associated with neurofibrillary tangles composed of hyperphosphorylated microtubule-associated protein, tau. β-N-methylamino-Lalanine (BMAA) has been suspected of being involved in the etiology of PD, but the mechanism by which BMAA leads to tau hyperphosphorylation is not known. We found a decrease in protein phosphatase 2A (PP2A) activity associated with an increase in inhibitory phosphorylation of its catalytic subunit PP2Ac at Tyr 307 and abnormal hyperphosphorylation of tau in brains of patients who had Guam PD. To test the possible involvement of BMAA in the etiopathogenesis of PD, we studied the effect of this environmental neurotoxin on PP2A activity and tau hyperphosphorylation in mouse primary neuronal cultures and metabolically active rat brain slices. BMAA treatment significantly decreased PP2A activity, with a concomitant increase in tau kinase activity resulting in elevated tau hyperphosphorylation at PP2A favorable sites. Moreover, we found an increase in the phosphorylation of PP2Ac at Tyr 307 in BMAA-treated rat brains. Pretreatment with metabotropic glutamate receptor 5 (mGluR5) and Src antagonists blocked the BMAAinduced inhibition of PP2A and the abnormal hyperphosphorylation of tau, indicating the involvement of an Src-dependent PP2A pathway. Coimmunoprecipitation experiments showed that BMAA treatment dissociated PP2Ac from mGluR5, making it available for phosphorylation at Tyr 307 . These findings suggest a scenario in which BMAA can lead to tau pathology by inhibiting PP2A through the activation of mGluR5, the consequent release of PP2Ac from the mGluR5-PP2A complex, and its phosphorylation at Tyr 307 by Src.Alzheimer's disease | amyotrophic lateral sclerosis | tauopathies | tau phosphorylation | cycad

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“…Moreover, I 2 PP2A controls gene transcription (24) by regulating histone acetylation (25) and is possibly involved in neuronal apoptotic pathways in AD brain (26). We have shown previously that both the mRNA and protein expressions of I 2 PP2A are up-regulated, and I 2 PP2A is selectively cleaved at Asn 175 into two fragments, N-terminal and C-terminal fragments (I 2NTF and I 2CTF ), by asparaginyl endopeptidase and is translocated from its primary localization in the nucleus to the cytoplasm (27)(28)(29). Because PP2A and Tau are localized in the cytoplasm, the increased neuronal cytoplasmic residing of I 2 PP2A in the AD brain leads to the inhibition of PP2A, Tau hyperphosphorylation, and formation of neurofibrillary tangles (28,30,31).…”

Section: Pp2amentioning

confidence: 99%

“…Subcellular Fractionation-Cytoplasmic and nuclear fractions were prepared from cells as described previously with minor modifications (29). Briefly, the cells were scraped and washed with cold PBS, and centrifuged at 200 ϫ g for 7 min.…”

Section: Pp2amentioning

confidence: 99%

Cytoplasmic Retention of Protein Phosphatase 2A Inhibitor 2 (I2PP2A) Induces Alzheimer-like Abnormal Hyperphosphorylation of Tau

Arif

Wei

Zhang

et al. 2014

Journal of Biological Chemistry

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Background: In Alzheimer brain, I 2 PP2A is translocated from the neuronal nucleus to the cytoplasm and promotes abnormal hyperphosphorylation of Tau. Results: Inactivation of nuclear localization signal (NLS) causes retention of I 2 PP2A in the cell cytoplasm, where it promotes Tau hyperphosphorylation by affecting PP2A signaling. Conclusion: Retention of I 2 PP2A in cell cytoplasm results in Tau hyperphosphorylation. Significance: The study provides potential tools for investigating Tau-based therapeutics.

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Activation of Asparaginyl Endopeptidase Leads to Tau Hyperphosphorylation in Alzheimer Disease

Cited by 112 publications

References 58 publications

Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia

Local Mitochondrial-Endolysosomal Microfusion Cleaves Voltage-Dependent Anion Channel 1 To Promote Survival in Hypoxia

Tau pathology involves protein phosphatase 2A in Parkinsonism-dementia of Guam

Cytoplasmic Retention of Protein Phosphatase 2A Inhibitor 2 (I2PP2A) Induces Alzheimer-like Abnormal Hyperphosphorylation of Tau

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