06699nas a2200169 4500008004100000245010700041210006900148260000800217520600300225100003606228700002906264700002706293700003406320700002606354700002506380856012406405 2024 eng d00aDual modification of tau by pseudophosphorylation and glycation does not enhance amorphous aggregation0 aDual modification of tau by pseudophosphorylation and glycation  cAPR3 a

Background/Aims:

 The neurofibrillary tangles consisting of Tau protein are an important pathology in Alzheimer’s disease. The paired helical filaments of Tau form most of the NFTs. These PHFs of Tau are found to carry numerous post-translational modifications, which stabilize them and aid in aggregation. The mechanistic function of Tau is to bind and stabilize the axonal microtubules. Hyperphosphorylation of Tau causes it to compromise its physiological function and accumulate in the neurons in the form of aggregates. Such residue-specific phosphorylation has been studied by employing Tau pseudophosphorylation mutants. But in addition to phosphorylation, several other modifications also aid in stabilizing the Tau PHF. Glycation is one such non-enzymatic PTM caused by sugars and their reactive intermediates. In this study, we employed the pseudophosphorylated Tau double mutants (262/404D, 262/396D, and 231/262) for studying their modification by methyl glyoxal, a reactive intermediate of glucose metabolism. 

Methods:

 We studied various biophysical properties like aggregation propensity, Advanced glycation end-product formation, and global conformation of the Tau with dual modifications. Our study includes the use of in vitro techniques e.g., ThS fluorescence assay, electron microscopy, CD spectroscopy, SDS-PAGE. 

Results:

 The overall result of the study suggest that the MG-induced Tau aggregation is influenced by the residue-specific Tau phosphorylation. 

Conclusion:

 In conclusion, the combinatorial effect of discreet PTMs on Tau function could lead to a better understanding of Tauopathy.

1 aChinnathambi, Subashchandrabose1 aSonawane, Shweta, Kishor1 aChandrashekar, Madhura1 aChidambaram, Hariharakrishnan1 aThulasiram, Shrivatsa1 aKulkarni, Mahesh, J. uhttps://library.ncl.res.in/content/dual-modification-tau-pseudophosphorylation-and-glycation-does-not-enhance-amorphous02340nas a2200169 4500008004100000022001400041245014000055210006900195260000900264300001600273490000700289520168600296100001901982700002602001700001702027856012602044 2025 eng d a2041-652000aThe critical helping hand of water: theory shows the way to obtain elusive, granular information about kinetic asymmetry driven systems0 acritical helping hand of water theory shows the way to obtain el cAUG  a14940-149550 v163 a

Kinetic asymmetry is crucial in chemical systems where the selective synthesis of one product over another, or the acceleration of specific reaction(s) is necessary. However, obtaining precise information with current experimental methods about the behavior of such systems as a function of time, substrate concentration and other relevant factors, is not possible. Computational chemistry provides a powerful means to address this problem. The current study unveils a two-pronged computational approach: (i) full quantum chemical studies with density functional theory (DFT), followed by (ii) stochastic simulations with a validated Gillespie algorithm (GA) (using representative model systems where necessary), to study the behavior of a kinetic asymmetry driven unidirectional molecular motor (1-phenylpyrrole2,2 `-dicarboxylic acid) (Nature, 2022, 604 (7904), 80-85). Our approach allows us to understand what is really taking place in the system, underlining the crucial role played by water molecules in facilitating the rotation of the motor. It is seen that water lubricates the motion by increasing the rotation rate constant of the final step by, remarkably, more than ten orders of magnitude! These insights further serve to explain the efficient rotation of the very recently reported gel-embedded molecular motor (Nature, 2025, 637 (8046), 594-600), providing an upper limit for the allowed rotation barrier in such systems, and thus also casts light into the functioning of bio-molecular motors. The current work therefore provides a template for carefully and properly studying a wide variety of important, kinetic asymmetry driven systems in the future.

1 aBajpai, Priyam1 aThulasiram, Shrivatsa1 aVanka, Kumar uhttps://library.ncl.res.in/content/critical-helping-hand-water-theory-shows-way-obtain-elusive-granular-information-about