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61.
Nicha Puangmalai Urmi Sengupta Nemil Bhatt Sagar Gaikwad Mauro Montalbano Arijit Bhuyan Stephanie Garcia Salome McAllen Minal Sonawane Cynthia Jerez Yingxin Zhao Rakez Kayed 《The Journal of biological chemistry》2022,298(4)
Ubiquitin-modified tau aggregates are abundantly found in human brains diagnosed with Alzheimer’s disease (AD) and other tauopathies. Soluble tau oligomers (TauO) are the most neurotoxic tau species that propagate pathology and elicit cognitive deficits, but whether ubiquitination contributes to tau formation and spreading is not fully understood. Here, we observed that K63-linked, but not K48-linked, ubiquitinated TauO accumulated at higher levels in AD brains compared with age-matched controls. Using mass spectrometry analyses, we identified 11 ubiquitinated sites on AD brain-derived TauO (AD TauO). We found that K63-linked TauO are associated with enhanced seeding activity and propagation in human tau-expressing primary neuronal and tau biosensor cells. Additionally, exposure of tau-inducible HEK cells to AD TauO with different ubiquitin linkages (wild type, K48, and K63) resulted in enhanced formation and secretion of K63-linked TauO, which was associated with impaired proteasome and lysosome functions. Multipathway analysis also revealed the involvement of K63-linked TauO in cell survival pathways, which are impaired in AD. Collectively, our study highlights the significance of selective TauO ubiquitination, which could influence tau aggregation, accumulation, and subsequent pathological propagation. The insights gained from this study hold great promise for targeted therapeutic intervention in AD and related tauopathies. 相似文献
62.
Mauro Montalbano Salome McAllen Urmi Sengupta Nicha Puangmalai Nemil Bhatt Anna Ellsworth Rakez Kayed 《Aging cell》2019,18(6)
The exact mechanisms leading to neurodegeneration in Alzheimer's disease (AD) and other tauopathies are not yet entirely understood. However, it is known that several RNA‐binding proteins (RBPs) form toxic aggregates and also interact with tau in such granules in tauopathies, including AD. The Musashi (MSI) family of RBPs, consisting of two homologues: Musashi1 and Musashi2, have not been extensively investigated in neurodegenerative diseases. Here, using a tau inducible HEK (iHEK) model we investigate whether MSI proteins contribute to the aggregation of toxic tau oligomers (TauO). Wild‐type and mutant P301L tau iHEK cells are used to study the effect of different tau variants on the cellular localization of MSI proteins. Interestingly, we observe that tau co‐localizes with MSI in the cytoplasm and nuclei, altering the nuclear transport of MSI. Furthermore, incremental changes in the size and density of nuclear MSI/tau foci are observed. We also report here that TauO interact with MSI to cause the formation of distinct nuclear aggregates. Moreover, tau/MSI aggregates induce structural changes to LaminB1, leading to nuclear instability. These results illustrate a possible mechanism of neurodegeneration mediated by the aggregation of MSI proteins and TauO, suggesting that MSI plays a critical role in cellular dysfunction. 相似文献
63.
G protein-activated inwardly rectifying potassium (GIRK) channels in 5-HT neurons are assumed to be principal effectors of 5-hydroxytryptamine 1A (5-HT1A) autoreceptors, but their pharmacology, subunit composition and the role in regulation of 5-HT neuron activity have not been fully elucidated. We sought for a pharmacological tool for assessing the functional role of GIRK channels in 5-HT neurons by characterizing the effects of drugs known to block GIRK channels in the submicromolar range of concentrations. Whole-cell voltage-clamp recording in brainstem slices were used to determine concentration-response relationships for the selected GIRK channel blockers on 5-HT1A autoreceptor-activated inwardly rectifying K+ conductance in rat dorsal raphe 5-HT neurons. 5-HT1A autoreceptor-activated GIRK conductance was completely blocked by the nonselective inwardly rectifying potassium channels blocker Ba2+ (EC50 = 9.4 μM, full block with 100 μM) and by SCH23390 (EC50 = 1.95 μM, full block with 30 μM). GIRK-specific blocker tertiapin-Q blocked 5-HT1A autoreceptor-activated GIRK conductance with high potency (EC50 = 33.6 nM), but incompletely, i.e. ~16% of total conductance resulted to be tertiapin-Q-resistant. U73343 and SCH28080, reported to block GIRK channels with submicromolar EC50s, were essentially ineffective in 5-HT neurons. Our data show that inwardly rectifying K+ channels coupled to 5-HT1A autoreceptors display pharmacological properties generally expected for neuronal GIRK channels, but different from GIRK1-GIRK2 heteromers, the predominant form of brain GIRK channels. Distinct pharmacological properties of GIRK channels in 5-HT neurons should be explored for the development of new therapeutic agents for mood disorders. 相似文献
64.
65.
Goebel P Montalbano A Ayers N Kompfner E Dickinson L Webb CF Feeney AJ 《Journal of immunology (Baltimore, Md. : 1950)》2002,169(5):2477-2487
66.
Background
Cyclic nucleotides are ubiquitous intracellular messengers. Until recently, the roles of cyclic nucleotides in plant cells have proven difficult to uncover. With an understanding of the protein domains which can bind cyclic nucleotides (CNB and GAF domains) we scanned the completed genomes of the higher plants Arabidopsis thaliana (mustard weed) and Oryza sativa (rice) for the effectors of these signalling molecules. 相似文献67.
Determining the evolutionary potential of a gene 总被引:4,自引:0,他引:4
In addition to information for current functions, the sequence of a gene
includes potential information for the evolution of new functions. The
wild-type ebgA (evolved beta-galactosidase) gene of Escherichia coli
encodes a virtually inactive beta-galactosidase, but that gene has the
potential to evolve sufficient activity to replace the lacZ gene for growth
on the beta-galactoside sugars lactose and lactulose. Experimental
evidence, which has suggested that the evolutionary potential of Ebg enzyme
is limited o two specific amino acid replacements, is limited to examining
the consequences of single base- substitutions. Thirteen
beta-galactosidases homologous with the Ebg beta-galactosidase are widely
dispersed, being found in gram-negative and gram-positive eubacteria and in
a eukaryote. A comparison of Ebg beta-galactosidase with those 13
beta-galactosidases shows that Ebg is part of an ancient clade that
diverged from the paralogous lacZ beta- galactosidase over 2 billion years
ago. Ebg differs from other members of its clade at only 2 of the 15
active-site residues, and the two mutations required for full Ebg
beta-galactosidase activity bring Ebg into conformity with the other
members of its clade. We conclude that either these are the only acceptable
amino acids at those positions, or all of the single-base-substitution
replacements that must arise as intermediates on the way to other
acceptable amino acids are so deleterious that they constitute a deep
selective valley that has not been traversed in over 2 billion years. The
evolutionary potential of Ebg is thus limited to those two replacements.
相似文献
68.
Cigarette smoke and non‐neuronal cholinergic system in the airway epithelium of COPD patients 下载免费PDF全文
69.
Kenneth C. Ehrlich Beverly G. Montalbano Deepak Bhatnagar Thomas E. Cleveland 《Fungal genetics and biology : FG & B》1998,23(3):279-287
AFLR, a zinc binuclear cluster DNA-binding protein, is required for activation of genes comprising the aflatoxin biosynthetic pathway inAspergillusspp. Transformation ofAspergillus parasiticuswith plasmids containing the intactaflRgene gave clones that produced fivefold more aflatoxin pathway metabolites than did the untransformed strain. When a 13-bp region in theaflRpromoter (positions −102 to −115 with respect to the ATG) was deleted, including a portion of a palindromic site previously shown to bind recombinant AFLR, metabolite production was 40% that of transformants with intactaflR.This result provides further evidence that this site may be involved in the autoregulation ofaflR.Overexpression of pathway genes could also result from increased quantities of AFLR titrating out a putative repressor protein. In AFLR, a 20-amino-acid acidic region near its carboxy-terminus resembles the region in yeast GAL4 required for GAL80 repressor binding. When 3 of the acidic amino acids in this region were deleted, levels of metabolites were even higher than those produced by transformants with intactaflR,as would be expected if repressor binding was suppressed in transformants containing this altered protein. Transformation with plasmids mutated at the AFLR zinc cluster (Cys to Trp at amino acid position 49) or at a putative nuclear localization signal region (RRARK deleted) gave clones with one-fifth the metabolite production of the untransformed fungus in spite of the transformants making the same or moreaflRmRNA. Since these transformants retained a copy of intactaflR,the latter results can be explained best by assuming that AFLR activates genes involved in aflatoxin production as a dimeric protein and that heterodimers containing both mutant and intact AFLR strands are inactive. 相似文献
70.