Structural Elements Regulating Amyloidogenesis: A Cholinesterase Model System

Polymerization into amyloid fibrils is a crucial step in the pathogenesis of neurodegenerative syndromes. Amyloid assembly is governed by properties of the sequence backbone and specific side-chain interactions, since fibrils from unrelated sequences possess similar structures and morphologies. Therefore, characterization of the structural determinants driving amyloid aggregation is of fundamental importance. We investigated the forces involved in the amyloid assembly of a model peptide derived from the oligomerization domain of acetylcholinesterase (AChE), AChE586-599, through the effect of single point mutations on β-sheet propensity, conformation, fibrilization, surfactant activity, oligomerization and fibril morphology. AChE586-599 was chosen due to its fibrilization tractability and AChE involvement in Alzheimer's disease. The results revealed how specific regions and residues can control AChE586-599 assembly. Hydrophobic and/or aromatic residues were crucial for maintaining a high β-strand propensity, for the conformational transition to β-sheet, and for the first stage of aggregation. We also demonstrated that positively charged side-chains might be involved in electrostatic interactions, which could control the transition to β-sheet, the oligomerization and assembly stability. Further interactions were also found to participate in the assembly. We showed that some residues were important for AChE586-599 surfactant activity and that amyloid assembly might preferentially occur at an air-water interface. Consistently with the experimental observations and assembly models for other amyloid systems, we propose a model for AChE586-599 assembly in which a steric-zipper formed through specific interactions (hydrophobic, electrostatic, cation-π, SH-aromatic, metal chelation and polar-polar) would maintain the β-sheets together. We also propose that the stacking between the strands in the β-sheets along the fiber axis could be stabilized through π-π interactions and metal chelation. The dissection of the specific molecular recognition driving AChE586-599 amyloid assembly has provided further knowledge on such poorly understood and complicated process, which could be applied to protein folding and the targeting of amyloid diseases

Whole-genome sequencing reveals new insights into age-related hearing loss: cumulative effects, pleiotropy and the role of selection

13noAge-related hearing loss (ARHL) is the most common sensory disorder in the elderly. Although not directly life threatening, it contributes to loss of autonomy and is associated with anxiety, depression and cognitive decline. To search for genetic risk factors underlying ARHL, a large whole-genome sequencing (WGS) approach has been carried out in a cohort of 212 cases and controls, both older than 50 years to select genes characterized by a burden of variants specific to cases or controls. Accordingly, the total variation load per gene was compared and two groups were detected: 375 genes more variable in cases and 371 more variable in controls. In both cases, Gene Ontology analysis showed that the largest enrichment for biological processes (fold > 5, p-value = 0.042) was the "sensory perception of sound", suggesting cumulative genetic effects were involved. Replication confirmed 141 genes, while additional analysis based on natural selection led to a prioritization of 21 genes. The majority of them (20 out of 21) showed positive expression in mouse cochlea cDNA and were associated with two functional pathways. Among them, two genes were previously associated with hearing (CSMD1 and PTRPD) and re-sequenced in a large Italian cohort of ARHL patients (N = 389). Results led to the identification of six coding variants not detected in cases so far, suggesting a possible protective role, which requires investigation. In conclusion, we show that this multistep strategy (WGS, selection, expression, pathway analysis and targeted re-sequencing) can provide major insights into the molecular characterization of complex diseases such as ARHL.openopenVuckovic, Dragana; Mezzavilla, Massimo; Cocca, Massimiliano; Morgan, Anna; Brumat, Marco; Catamo, Eulalia; Concas, Maria Pina; Biino, Ginevra; Franzè, Annamaria; Ambrosetti, Umberto; Pirastu, Mario; Gasparini, Paolo; Girotto, GiorgiaVuckovic, Dragana; Mezzavilla, Massimo; Cocca, Massimiliano; Morgan, Anna; Brumat, Marco; Catamo, Eulalia; Concas, Maria Pina; Biino, Ginevra; Franzè, Annamaria; Ambrosetti, Umberto; Pirastu, Mario; Gasparini, Paolo; Girotto, Giorgi

Hydrodynamic model for coherent nonlinear plasmonics

This chapter reviews recent advances in the investigation of the nonlinear optical properties of metallic nanostructures based on the hydrodynamic approach. The basic principles of this concept are introduced and various nonlinear phenomena, such as nonlinear harmonic generation at the nanoscale and soliton formation, are overviewed applying both perturbative analytical and approximation-free numerical methods