@article {48385,
	title = {Tryptophan-cardanol fluorescent nanoparticles inhibit alpha-synuclein aggregation and disrupt amyloid fibrils},
	journal = {Journal of Peptide Science},
	volume = {28},
	year = {2022},
	month = {APR},
	pages = {e3374},
	type = {Article},
	abstract = {<p>
	Protein misfolding and aggregation play a vital role in several human diseases such as Parkinson{\textquoteright}s, Alzheimer{\textquoteright}s, and prion diseases. The development of nanoparticles that modulate aggregation could be potential drug candidates for these neurodegenerative disorders. Parkinson{\textquoteright}s disease pathogenesis is closely associated with the accumulation of alpha-synuclein oligomers and fibrils in the substantia nigra of the brain. This report discusses the interactions of novel tryptophan-cardanol nanoparticles with alpha-synuclein protein monomers and fibrils. These nanoparticles could effectively disrupt alpha-synuclein fibrils and inhibit fibril formation at low concentrations such as 5 mu M. The tryptophan-cardanol nanoparticles inhibit fibril formation from unstructured protein resulting in spherical nanostructures. These nanoparticles could also disassemble amyloid fibrils; the complete disappearance of fibrils was evident after 48 h of incubation with tryptophan-cardanol. The transmission electron microscopy (TEM) micrographs after the incubation did not show any remnants of the peptide aggregates or oligomers. The thioflavin T fluorescence after the disassembly was diminished compared with that of fibrils also supports the inhibitory effect of the nanoparticles. Also, these nanoparticles did not reduce the viability of the SH-SY5Y cells. These findings suggest that the tryptophan-cardanol nanoparticles showed sufficiently high inhibitory activity and may have therapeutic potential for synucleinopathies.</p>
},
	keywords = {alpha-synuclein, amyloid fibrils, Cardanol, inhibitors, Tryptophan},
	issn = {1075-2617},
	doi = {10.1002/psc.3374},
	author = {Sunny, Lisni P. and Srikanth, Priya and Sunitha, Anju Kunhiraman and Tembulkar, Niyoti and Abraham, Jancy Nixon}
}
@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 = {<p>
	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.</p>
},
	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}
}
