Hypothesis on the Relationship Between the Change in Intracellular pH and Incidence of Sporadic Alzheimer's Disease or Vascular Dementia

Fang, Boyan; Wang, Dajiang; Huang, Mei-Feng; Yu, Guohua; Li, Hua

doi:10.3109/00207454.2010.505353

Cited by 77 publications

(75 citation statements)

References 35 publications

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“…Most cancers have constitutively increased pH i of ϳ0.4 units, which enables proliferation and metastasis (2)(3)(4). Conversely, neurodegenerative disorders, including Parkinson's and Alzheimer's diseases, are associated with constitutively decreased pH i , which is predicted to enable tau and ␤-amyloid aggregation as well as cell death (5,6). Finely tuned pH i homeostasis is maintained by dynamic changes in ion transporter activity that is sensitive to intracellular proton concentrations.…”

mentioning

confidence: 99%

A Histidine Cluster in the Cytoplasmic Domain of the Na-H Exchanger NHE1 Confers pH-sensitive Phospholipid Binding and Regulates Transporter Activity

Webb

White

Grillo-Hill

et al. 2016

Journal of Biological Chemistry

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Edited by Roger ColbranThe Na-H exchanger NHE1 contributes to intracellular pH (pH i ) homeostasis in normal cells and the constitutively increased pH i in cancer. NHE1 activity is allosterically regulated by intracellular protons, with greater activity at lower pH i . However, the molecular mechanism for pH-dependent NHE1 activity remains incompletely resolved. We report that an evolutionarily conserved cluster of histidine residues located in the C-terminal cytoplasmic domain between two phosphatidylinositol 4,5-bisphosphate binding sites (PI(4,5)P 2 ) of NHE1 confers pH-dependent PI(4,5)P 2 binding and regulates NHE1 activity. A GST fusion of the wild type C-terminal cytoplasmic domain of NHE1 showed increased maximum PI(4,5)P 2 binding at pH 7.0 compared with pH 7.5. However, pH-sensitive binding is abolished by substitutions of the His-rich cluster to arginine (RXXR3) or alanine (AXXA3), mimicking protonated and neutral histidine residues, respectively, and the RXXR3 mutant had significantly greater PI(4,5)P 2 binding than AXXA3. When expressed in cells, NHE1 activity and pH i were significantly increased with NHE1-RXXR3 and decreased with NHE1-AXXA3 compared with wild type NHE1. Additionally, fibroblasts expressing NHE1-RXXR3 had significantly more contractile actin filaments and focal adhesions compared with fibroblasts expressing wild type NHE1, consistent with increased pH i enabling cytoskeletal remodeling. These data identify a molecular mechanism for pH-sensitive PI(4,5)P 2 binding regulating NHE1 activity and suggest that the evolutionarily conserved cluster of four histidines in the proximal cytoplasmic domain of NHE1 may constitute a proton modifier site. Moreover, a constitutively activated NHE1-RXXR3 mutant is a new tool that will be useful for studying how increased pH i contributes to cell behaviors, most notably the biology of cancer cells.Intracellular pH (pH i ) homeostasis is generally maintained near neutral to compensate for metabolic changes and environmental stresses (1). However, dysregulated pH i is seen in a number of diseases. Most cancers have constitutively increased pH i of ϳ0.4 units, which enables proliferation and metastasis (2-4). Conversely, neurodegenerative disorders, including Parkinson's and Alzheimer's diseases, are associated with constitutively decreased pH i , which is predicted to enable tau and ␤-amyloid aggregation as well as cell death (5, 6). Finely tuned pH i homeostasis is maintained by dynamic changes in ion transporter activity that is sensitive to intracellular proton concentrations. However, the molecular mechanisms that mediate pH sensing by ion transporters remain poorly understood. The ubiquitously expressed Na-H exchanger isoform NHE1 4 contributes to maintaining pH i homeostasis by generating an electroneutral influx of extracellular Na ϩ and efflux of intracellular H ϩ at the plasma membrane. To maintain pH i homeostasis, NHE1 activity increases with acidic pH i and becomes nearly quiescent at neutral pH i . However, NHE1 activity can be increased a...

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confidence: 99%

A Histidine Cluster in the Cytoplasmic Domain of the Na-H Exchanger NHE1 Confers pH-sensitive Phospholipid Binding and Regulates Transporter Activity

Webb

White

Grillo-Hill

et al. 2016

Journal of Biological Chemistry

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“…Furthermore, ischemia and hypoxia, especially in association with hyperglycemia, lower brain pH. The fall in pH may result in a decrease in cellular metabolic activity, accumulation of acidic metabolites in the cell, and modulation of lysosomal enzymes (5)(6)(7).…”

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confidence: 99%

Activation of Asparaginyl Endopeptidase Leads to Tau Hyperphosphorylation in Alzheimer Disease

Basurto-Islas¹,

Grundke‐Iqbal²,

Tung³

et al. 2013

Journal of Biological Chemistry

107

102

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Background: Abnormal hyperphosphorylation of the microtubule-associated protein Tau is a hallmark of Alzheimer disease. Results: Acidosis of the brain activates and translocates asparaginyl endopeptidase from neuronal lysosomes to the cytoplasm where it leads to Tau hyperphosphorylation by inhibition of protein phosphatase 2A through cleavage of its inhibitor 2 into two active fragments. Conclusion: Activated asparaginyl endopeptidase causes Tau pathology. Significance: Brain acidosis can trigger Tau hyperphosphorylation.

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“…Especially it may be one of the reasons why Pin1 loses most of its activity below pH 5.0 [32] that the α-helix α3, which is close to the active site disappears. Many research worksreveal that the acidosis may be closely associated with some diseases [17][18][19][20][21]. The acid-induced structural changes of Pin1 confirm the important role of acidosis in the pathogenesis of Pin1-related diseases, such as cancers and AD.…”

Section: Discussionmentioning

confidence: 85%

“…Recently, our research confirms that Pin1 has a relatively high thermal stability [15]. On the other hand, the activity of an intracellular enzyme is closely associated with the intracellular pH, and many key enzymes will have altered activities under acidic conditions [16,17]. It is evident that the microenvironment acidification caused by metabolic alterations including glycolysis and intracellular alkalinisation is a main factor driving tumor progression, invasion, and metastases [18,19].…”

Section: Introductionmentioning

confidence: 71%

“…It is evident that the microenvironment acidification caused by metabolic alterations including glycolysis and intracellular alkalinisation is a main factor driving tumor progression, invasion, and metastases [18,19]. Acidosis also plays an important role in the development of Alzheimer's disease [17,[20][21][22]. For example, prolonged acidosis may markedly affect β-amyloid processing, resulting in the dysregulation of β-amyloid and subsequent plaque deposition and the death of neurons [21,23].…”

Section: Introductionmentioning

confidence: 99%

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Role of pH in structural changes for Pin1 protein: an insight from molecular dynamics study

Wang

Yao

et al. 2014

J Mol Model

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Pin1 protein is closely associated with the pathogenesis of cancers and Alzheimer's disease (AD). Previously, we have shown the acid-induced denaturation of Pin1 was determined by means of fluorescence emission, synchronous fluorescence etc., indicating an intermediate state around chromophores in Pin1 at about 4.0. Molecular dynamics simulations for the wild type Pin1 and its mutants were performed to explore the role of pH in the conformation changes of Pin1 protein. Our present study shows that one protein domain (PPIase domain) is more sensitive than the other one (WW domain) in Pin1 protein, and also our study shows that the integrality of the two conserve tryptophan in one domain (WW) is important in response to low pH. We arrive at the last result with the analysis of the protein root mean square distance and the analysis of the radius of gyration. The analysis of protein solvent accessible surface area values have proven our previous experiment result that there is an intermediate state around tryptophan residues at about pH 4.0. Moreover, acidic states of the protein can break the alpha-helixes in Pin1, especially the alpha-helix α3 close to active sites; as a result, Pin1 loses most of its activity at low pH. The results help us to understand the role of pH in Pin1, provide us insights into the conformation change at the atomic-level and emphasize the important role of decreased pH in the pathogenesis of some Pin1-related diseases, and support the therapeutic approach for the related Pin1 diseases by targeting acidosis and modifying the intracellular pH gradients.

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Hypothesis on the Relationship Between the Change in Intracellular pH and Incidence of Sporadic Alzheimer's Disease or Vascular Dementia

Cited by 77 publications

References 35 publications

A Histidine Cluster in the Cytoplasmic Domain of the Na-H Exchanger NHE1 Confers pH-sensitive Phospholipid Binding and Regulates Transporter Activity

A Histidine Cluster in the Cytoplasmic Domain of the Na-H Exchanger NHE1 Confers pH-sensitive Phospholipid Binding and Regulates Transporter Activity

Activation of Asparaginyl Endopeptidase Leads to Tau Hyperphosphorylation in Alzheimer Disease

Role of pH in structural changes for Pin1 protein: an insight from molecular dynamics study

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