02290nas a2200361 4500008004100000022001400041245011000055210006900165260007300234300001000307490000800317520103700325653002401362653004201386653002401428653002001452100003101472700001901503700002401522700002501546700002201571700001501593700002201608700001701630700001801647700001901665700002201684700001901706700002501725700002901750700001901779856013001798 2013 eng d a0301-010400aBasic structural motif and major biophysical properties of Amyloid-beta are encoded in the fragment 18-350 aBasic structural motif and major biophysical properties of Amylo aPO BOX 211, 1000 AE AMSTERDAM, NETHERLANDSbELSEVIER SCIENCE BVcAUG a80-870 v4223 a

Aggregation and misfolding of the amyloid beta (A beta) peptide is thought to initiate Alzheimer's disease (AD). Here we study the role played by its central segment (A beta(18-35)) in determining these properties. A beta(18-35) has a solubility of 18 mu M. The soluble fraction consists mainly of small oligomers, which have mixed beta-sheet and random coil structures. The monomer is mostly a random coil with some residual compactness. Aggregated A beta(18-35) forms fibrils of width 3.0 +/- 0.7 nm, which is consistent with a hairpin shape. Each of these properties has a close similarity to A beta(40). Remarkably, solid state NMR indicates that the fibrils also retain the secondary structure and tertiary contacts of A beta(40). This is the shortest fragment of A beta reported so far which preserves its fibrillar architecture, including the hairpin turn, as well as its solution phase conformational properties. Residues 18-35 should therefore be a key target of AD therapeutics. (C) 2013 Published by Elsevier B. V.

10aAlzheimer's disease10aFluorescence correlation spectroscopy10aProtein aggregation10aSolid-state NMR1 aChandrakesan, Muralidharan1 aSarkar, Bidyut1 aMithu, Venus, Singh1 aAbhyankar, Rajiv, M.1 aBhowmik, Debanjan1 aNag, Suman1 aSahoo, Bankanidhi1 aShah, Riddhi1 aGurav, Sushma1 aBanerjee, Raja1 aDandekar, Sucheta1 aJose, Jaya, C.1 aSengupta, Neelanjana1 aMadhu, Perunthiruthy, K.1 aMaiti, Sudipta uhttp://library.ncl.res.in/content/basic-structural-motif-and-major-biophysical-properties-amyloid-beta-are-encoded-fragment-002297nas a2200229 4500008004100000022001400041245011300055210006900168260000800237300001400245490000700259520149100266653002401757653002501781653001401806653001701820653002401837653001601861100002801877700003601905856012601941 2018 eng d a1387-287700aMulti-faceted role of melatonin in neuroprotection and amelioration of tau aggregates in alzheimer's disease0 aMultifaceted role of melatonin in neuroprotection and ameliorati cMAY a1481-14930 v623 a

Alzheimer's disease (AD) is one of the major age related neurodegenerative diseases whose pathology arises due to the presence of two distinct protein aggregates, viz., amyloid-beta plaques in extracellular matrix and tau neurofibrillary tangles in neurons. Multiple factors play a role in AD pathology, which includes familial mutations, oxidative stress, and post-translational modifications. Melatonin is an endocrine hormone, secreted during darkness, derived from tryptophan, and produced mainly by the pineal gland. It is an amphipathic molecule, which makes it suitable to cross not only blood-brain barrier, but also to enter several other subcellular compartments like mitochondria and endoplasmic reticulum. In this context, the neuroprotective effect of melatonin may be attributed to its role as an antioxidant. Melatonin's pleiotropic function as an antioxidant and neuroprotective agent has been widely studied. However, its direct effect on the aggregation of tau and amyloid-beta needs to be explored. Furthermore, an important aspect of its function is its ability to regulate the process of phosphorylation of tau by affecting the function of kinases and phosphatases. In this review, we are focusing on the pleiotropic function of melatonin on the aspect of its neuroprotective function in tau pathology, which includes antioxidant function, regulation of enzymes, including kinases and enzymes involved in free radical scavenging and mitochondrial protection.

10aAlzheimer's disease10ahyperphosphorylation10amelatonin10amitochondria10aProtein aggregation10atau protein1 aBalmik, Abhishek, Ankur1 aChinnathambi, Subashchandrabose uhttp://library.ncl.res.in/content/multi-faceted-role-melatonin-neuroprotection-and-amelioration-tau-aggregates-alzheimers02836nas a2200337 4500008004100000022001400041245018300055210006900238260000900307300001200316490000800328520165900336653001501995653002602010653002102036653003402057653002402091100002102115700001202136700002302148700002202171700001802193700002802211700002402239700002302263700002402286700001902310700002302329700002202352856012402374 2018 eng d a0013-468600aPorous reduced graphene oxide modified electrodes for the analysis of protein aggregation. Part 2: Application to the analysis of calcitonin containing pharmaceutical formulation0 aPorous reduced graphene oxide modified electrodes for the analys cMAR  a364-3720 v2663 a

In part 1 (A. Vasilescu et al., Porous reduced graphene oxide modified electrodes for the analysis of protein aggregation. Part 1: Lysozyme aggregation at pH 2 and 7.4 Electrochem. Acta, 254 (2017) 375 -383) we proposed porous reduced graphene oxide coated glassy carbon electrode (GC/prGO) in combination with differential pulse voltammetry as a new analytical tool for aggregation studies of proteins. Lysozyme was used as a model to follow its aggregation by electrochemical means at pH 2 and pH 7.4, leading to the formation of amyloid and amorphous aggregates, respectively. Part 2 of this work widens the scope of this approach by investigating a biopharmaceutical product, as the aggregation of peptide based drugs affects their therapeutic activity and can induce allergic reactions in patients. The salmon polypeptide calcitonin (sCT) was chosen as an example of a bioactive peptide with limited pharmaceutical potential due to a tendency to form cytotoxic aggregates and amyloid fibrils. For practical applications, screen printed electrodes (SPE) and flexible electrodes (FE) modified with polydiallyldimethylammonium (PDDA) and prGO by using the layer-by-layer deposition technique have been developed for the detection of sCT. The results indicate that these electrodes can differentiate between formation of amyloid aggregates of calcitonin (2 mg mL(-1)) in citrate buffer to no aggregation in acetate buffer. It was further demonstrated that these electrodes are able to analyze a pharmaceutical drug product of low potency, Miacalcic (8.3 mu g mL(-1)), where no aggregation was observed. (C) 2018 Elsevier Ltd. All rights reserved.

10aCalcitonin10aDisposable electrodes10aElectrochemistry10aPorous reduced graphene oxide10aProtein aggregation1 aVasilescu, Alina1 aYe, Ran1 aBoulahneche, Samia1 aLamraoui, Sabrina1 aJijie, Roxana1 aMedjram, Mohamed, Salah1 aGaspar, Szilveszter1 aSingh, Santosh, K.1 aKurungot, Sreekumar1 aMelinte, Sorin1 aBoukherroub, Rabah1 aSzunerits, Sabine uhttp://library.ncl.res.in/content/porous-reduced-graphene-oxide-modified-electrodes-analysis-protein-aggregation-part-201800nas a2200265 4500008004100000022001400041245007700055210006900132260000800201300001100209490000800220520092900228653002201157653001401179653002501193653002901218653002401247653001601271100002901287700002801316700002001344700002601364700003601390856010801426 2019 eng d a0003-986100aBaicalein suppresses repeat tau fibrillization by sequestering oligomers0 aBaicalein suppresses repeat tau fibrillization by sequestering o cOCT a1081190 v6753 a

Alzheimer's disease (AD) is a neurodegenerative disorder caused by protein misfolding, aggregation and accumulation in the brain. A large number of molecules are being screened against these pathogenic proteins but the focus for therapeutics is shifting towards the natural compounds as aggregation inhibitors, mainly due to their minimum adverse effects. Baicalein is a natural compound belonging to the class of flavonoids isolated from the Chinese herb Scutellaria baicalensis. Here we applied fluorescence, absorbance, microscopy, MALDI-TOF spectrophotometry and other biochemical techniques to investigate the interaction between Tau and Baicalein in vitro. We found the aggregation inhibitory properties of Baicalein for the repeat Tau. Overall, the potential of Baicalein in dissolving the preformed Tau oligomers as well as mature fibrils can be of utmost importance in therapeutics for Alzheimer's disease.

10aAlzheimer disease10aBaicalein10aMicrotubule assembly10aPaired helical filaments10aProtein aggregation10atau protein1 aSonawane, Shweta, Kishor1 aBalmik, Abhishek, Ankur1 aBoral, Debjyoti1 aRamasamy, Sureshkumar1 aChinnathambi, Subashchandrabose uhttp://library.ncl.res.in/content/baicalein-suppresses-repeat-tau-fibrillization-sequestering-oligomers02399nas a2200217 4500008004100000022001400041245011200055210006900167260000800236300001200244490000700256520161500263653001301878653003401891653003101925653002401956653003301980100002302013700001502036856013002051 2023 eng d a0887-358500aGoverning dynamics and preferential binding of the AXH domain influence the aggregation pathway of Ataxin-10 aGoverning dynamics and preferential binding of the AXH domain in cMAR a380-3940 v913 a

The present state of understanding the mechanism of Spinocerebellar Ataxia-1, a fatal neurodegenerative disease linked to the protein Ataxin-1 (ATXN1), is baffled by a set of self-contradictory, and hence, inconclusive observations. This fallacy poses a bottleneck to the effective designing of curable drugs as the field is currently missing the specific druggable site. To understand the fundamentals of pathogenesis, we tried to decipher the intricacies of the extremely complicated landscape by targeting the relevant species that supposedly dictate the structure-function paradigm. The atomic-level description and characterization of the dynamism of the systems reveal the existence of structural polymorphism in all the leading stakeholders of the overall system. The very existence of conformational heterogeneity in every species creates numerous possible combinations of favorable interactions because of the variability in segmental cross-talks and hence claims its role in the choice of routes between functional activity and dysfunctional disease-causing aggregation. Despite this emergent configurational diversity, there is a common mode of operative intermolecular forces that dictates the extent of stability of all the multimeric complexes due to the localized population of a specific type of residue. The present research proposes a dynamic switch mechanism between aggregability and functional activity, based on the logical interpretation of the estimated variables, which is practically dictated by the effective concentration of the interacting species involved in the cell.

10aAtaxin-110amolecular dynamics simulation10aneurodegenerative diseases10aProtein aggregation10aprotein misfolding disorders1 aTammara, Vaishnavi1 aDas, Atanu uhttp://library.ncl.res.in/content/governing-dynamics-and-preferential-binding-axh-domain-influence-aggregation-pathway-ataxin02703nas a2200253 4500008004100000022001400041245012700055210006900182260000800251300001400259490000700273520183800280653002002118653002702138653002202165653001902187653002402206653001402230100002202244700002202266700001502288700002402303856012202327 2024 eng d a1948-719300aPathological mutations D169G and P112H electrostatically aggravate the amyloidogenicity of the functional domain of TDP-430 aPathological mutations D169G and P112H electrostatically aggrava cNOV a4267-42830 v153 a

Aggregation of TDP-43 is linked to the pathogenesis of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Notably, electrostatic point mutations such as D169G and P112H, located within the highly conserved functional tandem RNA recognition motif (RRM) domains of the TDP-43 protein (TDP-43tRRM), have been identified in diseased patients as well. In this study, we address how the electrostatic mutations alter both the native state stability and aggregation propensity of TDP-43tRRM. The mutants D169G and P112H show increased chemical stability compared to the TDP-43tRRM at physiological pH. However, at low pH, both the mutants undergo a conformational change to form amyloid-like fibrils, though with variable rates-the P112H mutant being substantially faster than the other two sequences (TDP-43tRRM and D169G mutant) showing comparable rates. Moreover, among the three sequences, only the P112H mutant undergoes a strong ionic strength-dependent aggregability trend. These observations signify the substantial contribution of the excess charge of the P112H mutant to its unique aggregation process. Complementary simulated observables with atomistic resolution assign the experimentally observed sequence-, pH-, and ionic strength-dependent aggregability pattern to the degree of thermal lability of the mutation site-containing RRM1 domain and its extent of dynamical anticorrelation with the RRM2 domain whose combination eventually dictate the extent of generation of aggregation-prone partially unfolded conformational ensembles. Our choice of a specific charge-modulated pathogenic mutation-based experiment-simulation-combination approach unravels the otherwise hidden residue-wise contribution to the individual steps of this extremely complicated multistep aggregation process.

10aamyloid fibrils10aconformational changes10adisease mutations10aelectrostatics10aProtein aggregation10astability1 aPillai, Meenakshi1 aPatil, Anjali, D.1 aDas, Atanu1 aJha, Santosh, Kumar uhttp://library.ncl.res.in/content/pathological-mutations-d169g-and-p112h-electrostatically-aggravate-amyloidogenicity