@article {46615, title = {Effect of tert-alcohol functional imidazolium salts on oligomerization and fibrillization of amyloid beta (1-42) peptide}, journal = {Biophysical Chemistry}, volume = {267}, year = {2020}, month = {DEC}, pages = {106480}, type = {Article}, abstract = {

Imidazolium based IL{\textquoteright}s has gained vast interest in developing biological applications. Oligomerization and fibrillization of amyloid beta (1-42) peptide are mainly responsible for the extra-neuronal deposition of amyloid fibrils in neurodegenerative disorders like Alzheimer{\textquoteright}s disease (AD). Here, we report an effect of tert-BuOH-functional imidazolium ILs on oligomerization and fibrillization of amyloid beta (1-42) Peptide in vitro. In this study, a series of these [alkyl-(t)OHim][OMs] ILs with methyl sulphonate counter anion by varying alkyl chains were used. Among the seven protic ILs, four showed strong binding and inhibition activity for the formation of amyloid beta (1-42) aggregation by using Thioflavin T fluorescence binding assay. The secondary structural analysis of the peptide, pre-incubated with active ILs shows the loss of ordered beta-sheet amyloid structure. The longer alkyl chain ILs showed that an increased in amyloid binding and hence an inhibition effect on amyloid aggregation was enhanced. Thus, we propose that ILs could be presented as potential candidates for therapeutic intervention against Alzheimer{\textquoteright}s disease (AD).

}, keywords = {Aggregation, Amyloid beta (1-42) peptide, Biofilm inhibitor, Imidazolium ionic liquid}, issn = {0301-4622}, doi = {10.1016/j.bpc.2020.106480}, author = {Said, Madhukar S. and Navale, Govinda R. and Yadav, Ashok and Khonde, Nilesh and Shinde, Sandip S. and Jha, Anjali} } @article {49337, title = {DNA-mediated formation of phase-separated coacervates of the nucleic acid-binding domain of TAR DNA-binding protein (TDP-43) prevents its amyloid-like misfolding}, journal = {ACS Chemical Neuroscience}, volume = {15}, year = {2024}, month = {OCT }, pages = {4105-4122}, type = {Article}, abstract = {

Sequestration of protein molecules and nucleic acids to stress granules is one of the most promising strategies that cells employ to protect themselves from stress. In vitro, studies suggest that the nucleic acid-binding domain of TDP-43 (TDP-43tRRM) undergoes amyloid-like aggregation to beta-sheet-rich structures in low pH stress. In contrast, we observed that the TDP-43tRRM undergoes complex coacervation in the presence of ssDNA to a dense and light phase, preventing its amyloid-like aggregation. The soluble light phase consists of monomeric native-like TDP-43tRRM. The microscopic data suggest that the dense phase consists of spherical coacervates with limited internal dynamics. We performed multiparametric analysis by employing various biophysical techniques and found that complex coacervation depends on the concentration and ratio of the participating biomolecules and is driven by multivalent interactions. The modulation of these forces due to environmental conditions or disease mutations regulates the extent of coacervation, and the weakening of interactions between TDP-43tRRM and ssDNA leads to amyloid-like aggregation of TDP-43tRRM. Our results highlight a competition among the native state, amyloid-like aggregates, and complex coacervates tuned by various environmental factors. Together, our results illuminate an alternate function of TDP-43tRRM in response to pH stress in the presence of the ssDNA.

}, keywords = {amyloid-likeaggregation, complex coacervation, DNA-protein interactions, Dynamics, pH stress, TDP-43}, issn = {1948-7193}, doi = {10.1021/acschemneuro.4c00117}, author = {Patni, Divya and Patil, Anjali D. and Kirmire, Mona S. and Jha, Anjali and Jha, Santosh Kumar} } @article {50072, title = {Structural and mechanistic heterogeneity of the phase separation and aggregation of full-length TDP-43 is governed by environmental conditions}, journal = {ACS Chemical Neuroscience}, volume = {17}, year = {2026}, month = {APR}, pages = {1362-1374}, type = {Article}, abstract = {

TAR DNA-binding protein 43 (TDP-43) is an essential physiological protein implicated in several fatal neurodegenerative disorders. Interestingly, the nature of TDP-43 aggregates varies across patients and disease conditions, suggesting an underlying heterogeneity in its self-assembly behavior. In this study, we investigated two native-like states of full-length TDP-43: the native dimer (N form) and the native-like oligomer (O form). These are compact, folded states with similar secondary structures but differ in size. We found that the N and O forms respond differently to external perturbations and form distinct self-assemblies under stress conditions. Under electrostatic stress, both N and O forms undergo phase separation but produce condensates with markedly different morphologies and dynamics. The underlying mechanisms driving their phase separation are different. Under thermal stress, both forms convert into amyloid aggregates, but again with clearly different morphologies, biochemical properties, and aggregation pathways. These results demonstrate that multiple conformations of TDP-43 respond to distinct perturbations by assembling into structurally and mechanistically different higher-order assemblies. Our findings highlight how the interplay among the structural state, solvation environment, and self-assembly mechanism governs the heterogeneity of TDP-43 assemblies, offering new insights into their physiological roles and pathological relevance. This study suggests that the heterogeneity observed in patients associated with TDP-43 aggregation may arise from differences in the cellular stresses experienced by the protein and the corresponding assembly mechanisms engaged.

}, keywords = {Amyloid-like aggregation, molecular mechanism of phase separation, native-like phase separation, Self-assembly}, issn = {1948-7193}, doi = {10.1021/acschemneuro.5c01003}, author = {Doke, Abhilasha A. and Kirmire, Mona S. and Jha, Anjali and Jha, Santosh Kumar} }