ABSTRACT
Hydration plays a crucial role in the refolding of intrinsically disordered proteins into amyloid fibrils; however, the specific interactions between water and protein that may contribute to this process are still unknown. In our previous studies of alpha-synuclein (aSyn), we have shown that waters confined in fibril cavities are stabilizing features of this pathological fold; and that amino acids that hydrogen bond with these confined waters modulate primary and seeded aggregation. Here, we extend our aSyn molecular dynamics (MD) simulations with three new polymorphs and correlate MD trajectory information with known post-translational modifications (PTMs) and experimental data. We show that cavity residues are more evolutionarily conserved than non-cavity residues and are enriched with PTM sites. As expected, the confinement within hydrophilic cavities results in more stably hydrated amino acids. Interestingly, cavity PTM sites display the longest protein-water hydrogen bond lifetimes, three-fold greater than non-PTM cavity sites. Utilizing the deep mutational screen dataset by Newberry et al. and the Thioflavin T aggregation review by Pancoe et al. parsed using a fibril cavity/non-cavity definition, we show that hydrophobic changes to amino acids in cavities have a larger effect on fitness and aggregation rate than residues outside cavities, supporting our hypothesis that these sites are involved in the inhibition of aSyn toxic fibrillization. Finally, we expand our study to include analysis of fibril structures of tau, FUS, TDP-43, prion, and hnRNPA1; all of which contained hydrated cavities, with tau, FUS, and TDP-43 recapitulating our PTM results in aSyn fibril cavities.
Subject(s)
DNA-Binding Proteins , Hydrogen Bonding , Hydrophobic and Hydrophilic Interactions , Molecular Dynamics Simulation , Protein Processing, Post-Translational , RNA-Binding Protein FUS , alpha-Synuclein , tau Proteins , alpha-Synuclein/chemistry , alpha-Synuclein/metabolism , alpha-Synuclein/genetics , Humans , tau Proteins/chemistry , tau Proteins/metabolism , tau Proteins/genetics , DNA-Binding Proteins/chemistry , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , RNA-Binding Protein FUS/chemistry , RNA-Binding Protein FUS/metabolism , RNA-Binding Protein FUS/genetics , Amyloid/chemistry , Amyloid/metabolism , Water/chemistry , Water/metabolism , MutationABSTRACT
Background: Challenging behaviours are common among children and adolescents with intellectual disabilities. Such behaviours often result in poor quality of life outcomes such as physical injury, difficulties with relationships and community integration. Aim: This systematic review aimed to synthesise evidence from studies that assessed the effect of interventions used to reduce/manage challenging behaviour among children with intellectual disabilities in community settings. Methods: Studies published between January 2015 and January 2021 were sought from five electronic databases. The quality of studies was assessed, and a narrative synthesis was conducted. Results: A total of 11 studies were included which utilised various non-pharmacological interventions including multi-model interventions, microswitch technology, cognitive behavioural therapy, art, music and illustrated stories. Microswitch cluster technology was the most used intervention. Studies using pharmacological interventions were not retrieved. Results indicated that a person-centred planning approach was key to offering individualised treatment. Conclusions: The superiority of one intervention or a combination of interventions could not be determined from this review given the heterogeneity of studies. Future research is required to explore the use and effects of pharmacological interventions to compare outcomes and improve quality of care of children with intellectual disabilities.
