Sorcin Activates the Brain PMCA and Blocks the Inhibitory Effects of Molecular Markers of Alzheimer's Disease on the Pump Activity.
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ABSTRACT:
SUBMITTER: Berrocal M
PROVIDER: S-EPMC8200006 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Methylene blue (MB) is a synthetic phenothiazine dye that, in the last years, has generated much debate about whether it could be a useful therapeutic drug for tau-related pathologies, such as Alzheimer's disease (AD). However, the molecular mechanism of action is far from clear. Recently we reported that MB activates the plasma membrane Ca2+-ATPase (PMCA) in membranes from human and pig tissues and from cells cultures, and that it could protect against inactivation of PMCA by amyloid β-peptide (Aβ). The purpose of the present study is to further examine whether the MB could also modulate the inhibitory effect of tau, another key molecular marker of AD, on PMCA activity. By using kinetic assays in membranes from several tissues and cell cultures, we found that this phenothiazine was able to block and even to completely reverse the inhibitory effect of tau on PMCA. The results of this work point out that MB could mediate the toxic effect of tau related to the deregulation of calcium homeostasis by blocking the impairment of PMCA activity by tau. We then could conclude that MB could interfere with the toxic effects of tau by restoring the function of PMCA pump as a fine tuner of calcium homeostasis.
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Project description:Sorcin (Soluble resistance related calcium binding protein) is a small soluble penta EF family (PEF) of calcium (Ca2+) binding protein (22,000 Da). It has been reported to play crucial roles in the regulation of calcium homeostasis, apoptosis, vesicle trafficking, cancer development, and multidrug resistance (MDR). Overexpression of sorcin has been reported to be associated with different cancers such as breast cancer, colorectal cancer, gastric cancer, leukemia, lung cancer, nasopharyngeal cancer, ovarian cancer, etc. Essentially, expression of sorcin has been found to be elevated in cancer cells as compared to normal cells, indicating that it has prominent role in cancer. Moreover, sorcin was found to be the regulator of various proteins that has an association with carcinogenesis including NF-?B, STAT3, Akt, ERK1/2, VEGF, MMPs, caspases, etc. Sorcin was also found to regulate apoptosis, as silencing of the same resulted in increased levels of proapoptotic genes and induced mitochondrial apoptotic pathway in cancer. Interestingly, mutations in the sorcin gene have been closely linked with poor overall survival in bladder cancer, brain lower-grade glioma, glioblastoma, glioblastoma multiforme, kidney renal clear cell carcinoma, and stomach adenocarcinoma. Additionally, overexpression of sorcin was also found to induce MDR against different chemotherapeutic drugs. All these findings mark the importance of sorcin in cancer development and MDR. Therefore, there is urgent need to explore the functional mechanism of sorcin and to analyze whether silencing of sorcin would able to chemosensitize MDR cells. The current review summarizes the structure, expression, and functions of sorcin and its importance in the regulation of various malignancies and MDR.
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Project description:The transport of calcium to the extracellular space carried out by plasma membrane Ca(2+) pumps (PMCAs) is essential for maintaining low Ca(2+) concentrations in the cytosol of eukaryotic cells. The activity of PMCAs is controlled by autoinhibition. Autoinhibition is relieved by the binding of Ca(2+)-calmodulin to the calmodulin-binding autoinhibitory sequence, which in the human PMCA is located in the C-terminal segment and results in a PMCA of high maximal velocity of transport and high affinity for Ca(2+). Autoinhibition involves the intramolecular interaction between the autoinhibitory domain and a not well defined region of the molecule near the catalytic site. Here we show that the fusion of GFP to the C terminus of the h4xb PMCA causes partial loss of autoinhibition by specifically increasing the Vmax. Mutation of residue Glu(99) to Lys in the cytosolic portion of the M1 transmembrane helix at the other end of the molecule brought the Vmax of the h4xb PMCA to near that of the calmodulin-activated enzyme without increasing the apparent affinity for Ca(2+). Altogether, the results suggest that the autoinhibitory interaction of the extreme C-terminal segment of the h4 PMCA is disturbed by changes of negatively charged residues of the N-terminal region. This would be consistent with a recently proposed model of an autoinhibited form of the plant ACA8 pump, although some differences are noted.
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Project description:The exposure of the plasma membrane calcium pump (PMCA) to the surrounding phospholipids was assessed by measuring the incorporation of the photoactivatable phosphatidylcholine analog [(125)I]TID-PC/16 to the protein. In the presence of Ca(2+) both calmodulin (CaM) and phosphatidic acid (PA) greatly decreased the incorporation of [(125)I]TID-PC/16 to PMCA. Proteolysis of PMCA with V8 protease results in three main fragments: N, which includes transmembrane segments M1 and M2; M, which includes M3 and M4; and C, which includes M5 to M10. CaM decreased the level of incorporation of [(125)I]TID-PC/16 to fragments M and C, whereas phosphatidic acid decreased the incorporation of [(125)I]TID-PC/16 to fragments N and M. This suggests that the conformational changes induced by binding of CaM or PA extend to the adjacent transmembrane domains. Interestingly, this result also denotes differences between the active conformations produced by CaM and PA. To verify this point, we measured resonance energy transfer between PMCA labeled with eosin isothiocyanate at the ATP-binding site and the phospholipid RhoPE included in PMCA micelles. CaM decreased the efficiency of the energy transfer between these two probes, whereas PA did not. This result indicates that activation by CaM increases the distance between the ATP-binding site and the membrane, but PA does not affect this distance. Our results disclose main differences between PMCA conformations induced by CaM or PA and show that those differences involve transmembrane regions.
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Project description:Ca2+ signals, which facilitate pluripotent changes in cell fate, reflect the balance between cation entry and export. We found that overexpression of either isoform of the Ca2+-extruding plasma membrane calcium ATPase 4 (PMCA4) pump in Jurkat T cells unexpectedly increased activation of the Ca2+-dependent transcription factor nuclear factor of activated T cells (NFAT). Coexpression of the endoplasmic reticulum-resident Ca2+ sensor stromal interaction molecule 1 (STIM1) with the PMCA4b splice variant further enhanced NFAT activity; however, coexpression with PMCA4a depressed NFAT. No PMCA4 splice variant dependence in STIM1 association was observed, whereas partner of STIM1 (POST) preferentially associated with PMCA4b over PMCA4a, which enhanced, rather than inhibited, PMCA4 function. A comparison of global and near-membrane cytosolic Ca2+ abundances during store-operated Ca2+ entry revealed that PMCA4 markedly depressed near-membrane Ca2+ concentrations, particularly when PMCA4b was coexpressed with STIM1. PMCA4b closely associated with both POST and the store-operated Ca2+ channel Orai1. Furthermore, POST knockdown increased the near-membrane Ca2+ concentration, inhibiting the global cytosolic Ca2+ increase. These observations reveal an unexpected role for POST in coupling PMCA4 to Orai1 to promote Ca2+ entry during T cell activation through Ca2+ disinhibition.
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Project description:Current amyloid beta-targeting approaches for Alzheimer's disease (AD) therapeutics only slow cognitive decline for small numbers of patients. This limited efficacy exists because AD is a multifactorial disease whose pathological mechanism(s) and diagnostic biomarkers are largely unknown. Here we report a new mechanism of AD pathogenesis in which the histone methyltransferase G9a noncanonically regulates translation of a hippocampal proteome that defines the proteopathic nature of AD. Accordingly, we developed a novel brain-penetrant inhibitor of G9a, MS1262, across the blood-brain barrier to block this G9a-regulated, proteopathologic mechanism. Intermittent MS1262 treatment of multiple AD mouse models consistently restored both cognitive and noncognitive functions to healthy levels. Comparison of proteomic/phosphoproteomic analyses of MS1262-treated AD mice with human AD patient data identified multiple pathological brain pathways that elaborate amyloid beta and neurofibrillary tangles as well as blood coagulation, from which biomarkers of early stage of AD including SMOC1 were found to be affected by MS1262 treatment. Notably, these results indicated that MS1262 treatment may reduce or avoid the risk of blood clot burst for brain bleeding or a stroke. This mouse-to-human conservation of G9a-translated AD proteopathology suggests that the global, multifaceted effects of MS1262 in mice could extend to relieve all symptoms of AD patients with minimum side effect. In addition, our mechanistically derived biomarkers can be used for stage-specific AD diagnosis and companion diagnosis of individualized drug effects.
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Project description:ObjectivePeripheral protein biomarkers of Alzheimer's disease (AD) may help identify novel treatment avenues by allowing early diagnosis, recruitment to clinical trials, and treatment initiation. The purpose of this review was to determine which proteins have been found to be differentially expressed in the AD brain and whether these proteins are also found within the blood of AD patients.MethodsA two-stage approach was conducted. The first stage involved conducting a systematic search to identify discovery-based brain proteomic studies of AD. The second stage involved comparing whether proteins found to be differentially expressed in AD brain were also differentially expressed in the blood.ResultsAcross 11 discovery based brain proteomic studies 371 proteins were at different levels in the AD brain. Nine proteins were frequently found, defined as appearing in at least three separate studies. Of these proteins heat-shock cognate 71 kDa, ubiquitin carboxyl-terminal hydrolase isozyme L1, and 2',3'-cyclic nucleotide 3' phosphodiesterase alone were found to share a consistent direction of change, being consistently upregulated in studies they appeared in. Eighteen proteins seen as being differentially expressed within the AD brain were present in blood proteomic studies of AD. Only complement C4a was seen multiple times within both the blood and brain proteomic studies.InterpretationWe report a number of proteins appearing in both the blood and brain of AD patients. Of these proteins, C4a may be a good candidate for further follow-up in large-scale replication efforts.
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Project description:BackgroundAlzheimer's disease (AD) is a complex neurodegenerative disorder and the most common type of dementia. AD is characterized by a decline of cognitive function and brain atrophy, and is highly heritable with estimated heritability ranging from 60 to 80[Formula: see text]. The most straightforward and widely used strategy to identify AD genetic basis is to perform genome-wide association study (GWAS) of the case-control diagnostic status. These GWAS studies have identified over 50 AD related susceptibility loci. Recently, imaging genetics has emerged as a new field where brain imaging measures are studied as quantitative traits to detect genetic factors. Given that many imaging genetics studies did not involve the diagnostic outcome in the analysis, the identified imaging or genetic markers may not be related or specific to the disease outcome.ResultsWe propose a novel method to identify disease-related genetic variants enriched by imaging endophenotypes, which are the imaging traits associated with both genetic factors and disease status. Our analysis consists of three steps: (1) map the effects of a genetic variant (e.g., single nucleotide polymorphism or SNP) onto imaging traits across the brain using a linear regression model, (2) map the effects of a diagnosis phenotype onto imaging traits across the brain using a linear regression model, and (3) detect SNP-diagnosis association via correlating the SNP effects with the diagnostic effects on the brain-wide imaging traits. We demonstrate the promise of our approach by applying it to the Alzheimer's Disease Neuroimaging Initiative database. Among 54 AD related susceptibility loci reported in prior large-scale AD GWAS, our approach identifies 41 of those from a much smaller study cohort while the standard association approaches identify only two of those. Clearly, the proposed imaging endophenotype enriched approach can reveal promising AD genetic variants undetectable using the traditional method.ConclusionWe have proposed a novel method to identify AD genetic variants enriched by brain-wide imaging endophenotypes. This approach can not only boost detection power, but also reveal interesting biological pathways from genetic determinants to intermediate brain traits and to phenotypic AD outcomes.
| S-EPMC9344647 | biostudies-literature
Project description:This study assessed relationships among white matter hyperintensities (WMH), cerebrospinal fluid (CSF), Alzheimer's disease (AD) pathology markers, and brain volume loss. Subjects included 197 controls, 331 individuals with mild cognitive impairment (MCI), and 146 individuals with AD with serial volumetric 1.5-T MRI. CSF A?1-42 (n = 351) and tau (n = 346) were measured. Brain volume change was quantified using the boundary shift integral (BSI). We assessed the association between baseline WMH volume and annualized BSI, adjusting for intracranial volume. We also performed multiple regression analyses in the CSF subset, assessing the relationships of WMH and A?1-42 and/or tau with BSI. WMH burden was positively associated with BSI in controls (p = 0.02) but not MCI or AD. In multivariable models, WMH (p = 0.003) and A?1-42 (p = 0.001) were independently associated with BSI in controls; in MCI A?1-42 (p < 0.001) and tau (p = 0.04) were associated with BSI. There was no evidence of independent effects of WMH or CSF measures on BSI in AD. These data support findings that vascular damage is associated with increased brain atrophy in the context of AD pathology in pre-dementia stages.
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