@article { ISI:000324309600011, title = {Basic structural motif and major biophysical properties of Amyloid-beta are encoded in the fragment 18-35}, journal = {Chemical Physics}, volume = {422}, number = {SI}, year = {2013}, month = {AUG}, pages = {80-87}, publisher = {ELSEVIER SCIENCE BV}, address = {PO BOX 211, 1000 AE AMSTERDAM, NETHERLANDS}, abstract = {

Aggregation and misfolding of the amyloid beta (A beta) peptide is thought to initiate Alzheimer{\textquoteright}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.

}, keywords = {Alzheimer{\textquoteright}s disease, Fluorescence correlation spectroscopy, Protein aggregation, Solid-state NMR}, issn = {0301-0104}, doi = {10.1016/j.chemphys.2013.01.010}, author = {Chandrakesan, Muralidharan and Sarkar, Bidyut and Mithu, Venus Singh and Rajiv M. Abhyankar and Bhowmik, Debanjan and Nag, Suman and Sahoo, Bankanidhi and Shah, Riddhi and Gurav, Sushma and Banerjee, Raja and Dandekar, Sucheta and Jose, Jaya C. and Sengupta, Neelanjana and Madhu, Perunthiruthy K. and Maiti, Sudipta} } @article {44532, title = {Multi-faceted role of melatonin in neuroprotection and amelioration of tau aggregates in alzheimer{\textquoteright}s disease}, journal = {Journal of Alzheimers Disease}, volume = {62}, year = {2018}, month = {MAY}, pages = {1481-1493}, abstract = {

Alzheimer{\textquoteright}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{\textquoteright}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.

}, keywords = {Alzheimer{\textquoteright}s disease, hyperphosphorylation, melatonin, mitochondria, Protein aggregation, tau protein}, issn = {1387-2877}, doi = {10.3233/JAD-170900}, author = {Balmik, Abhishek Ankur and Chinnathambi, Subashchandrabose} } @article {44552, title = {Porous reduced graphene oxide modified electrodes for the analysis of protein aggregation. Part 2: Application to the analysis of calcitonin containing pharmaceutical formulation}, journal = {Electrochimica Acta}, volume = {266}, year = {2018}, month = {MAR }, pages = {364-372}, abstract = {

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.

}, keywords = {Calcitonin, Disposable electrodes, Electrochemistry, Porous reduced graphene oxide, Protein aggregation}, issn = {0013-4686}, doi = {10.1016/j.electacta.2018.02.038}, author = {Vasilescu, Alina and Ye, Ran and Boulahneche, Samia and Lamraoui, Sabrina and Jijie, Roxana and Medjram, Mohamed Salah and Gaspar, Szilveszter and Singh, Santosh K. and Kurungot, Sreekumar and Melinte, Sorin and Boukherroub, Rabah and Szunerits, Sabine} } @article {47164, title = {Baicalein suppresses repeat tau fibrillization by sequestering oligomers}, journal = {Archives of Biochemistry and Biophysics}, volume = {675}, year = {2019}, month = {OCT}, pages = {108119}, type = {Article}, abstract = {

Alzheimer{\textquoteright}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{\textquoteright}s disease.

}, keywords = {Alzheimer disease, Baicalein, Microtubule assembly, Paired helical filaments, Protein aggregation, tau protein}, issn = {0003-9861}, doi = {10.1016/j.abb.2019.108119}, author = {Sonawane, Shweta Kishor and Balmik, Abhishek Ankur and Boral, Debjyoti and Ramasamy, Sureshkumar and Chinnathambi, Subashchandrabose} } @article {48447, title = {Governing dynamics and preferential binding of the AXH domain influence the aggregation pathway of Ataxin-1}, journal = {Proteins-Structure Function and Bioinformatics}, volume = {91}, year = {2023}, month = {MAR}, pages = {380-394}, type = {Article}, abstract = {

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.

}, keywords = {Ataxin-1, molecular dynamics simulation, neurodegenerative diseases, Protein aggregation, protein misfolding disorders}, issn = {0887-3585}, doi = {10.1002/prot.26436}, author = {Tammara, Vaishnavi and Das, Atanu} } @article {49191, title = {Pathological mutations D169G and P112H electrostatically aggravate the amyloidogenicity of the functional domain of TDP-43}, journal = {ACS Chemical Neuroscience}, volume = {15}, year = {2024}, month = {NOV}, pages = {4267-4283}, type = {Article}, abstract = {

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.

}, keywords = {amyloid fibrils, conformational changes, disease mutations, electrostatics, Protein aggregation, stability}, issn = {1948-7193}, doi = {10.1021/acschemneuro.4c00372}, author = {Pillai, Meenakshi and Patil, Anjali D. and Das, Atanu and Jha, Santosh Kumar} }