02384nas a2200253   4500008004100000022001400041245011400055210006900169260000800238300001000246490000700256520154000263653002001803653002001823653001301843653001501856653001501871100002101886700002001907700003001927700002201957700002601979856012502005       2022                        eng d  a1075-261700aTryptophan-cardanol fluorescent nanoparticles inhibit alpha-synuclein aggregation and disrupt amyloid fibrils0 aTryptophancardanol fluorescent nanoparticles inhibit alphasynucl  cAPR  ae33740 v283 a<p>
	Protein misfolding and aggregation play a vital role in several human diseases such as Parkinson's, Alzheimer's, and prion diseases. The development of nanoparticles that modulate aggregation could be potential drug candidates for these neurodegenerative disorders. Parkinson'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>
10aalpha-synuclein10aamyloid fibrils10aCardanol10ainhibitors10aTryptophan1 aSunny, Lisni, P.1 aSrikanth, Priya1 aSunitha, Anju, Kunhiraman1 aTembulkar, Niyoti1 aAbraham, Jancy, Nixon  uhttps://library.ncl.res.in/content/tryptophan-cardanol-fluorescent-nanoparticles-inhibit-alpha-synuclein-aggregation-and02704nas a2200253   4500008004100000022001400041245012700055210006900182260000800251300001400259490000700273520183800280653002002118653002702138653002202165653001902187653002402206653001402230100002202244700002202266700001502288700002402303856012302327       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<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>
10aamyloid fibrils10aconformational changes10adisease mutations10aelectrostatics10aProtein aggregation10astability1 aPillai, Meenakshi1 aPatil, Anjali, D.1 aDas, Atanu1 aJha, Santosh, Kumar  uhttps://library.ncl.res.in/content/pathological-mutations-d169g-and-p112h-electrostatically-aggravate-amyloidogenicity