Protein Misfolding Diseases

Abstract

The majority of protein molecules must fold into defined three-dimensional structures to acquire functional activity. However, protein chains can adopt a multitude of conformational states, and their biologically active conformation is often only marginally stable. Metastable proteins tend to populate misfolded species that are prone to forming toxic aggregates, including soluble oligomers and fibrillar amyloid deposits, which are linked with neurodegeneration in Alzheimer and Parkinson disease, and many other pathologies. To prevent or regulate protein aggregation, all cells contain an extensive protein homeostasis (or proteostasis) network comprising molecular chaperones and other factors. These defense systems tend to decline during aging, facilitating the manifestation of aggregate deposition diseases. This volume of the Annual Review of Biochemistry contains a set of three articles addressing our current understanding of the structures of pathological protein aggregates and their associated disease mechanisms. These articles also discuss recent insights into the strategies cells have evolved to neutralize toxic aggregates by sequestering them in specific cellular locations.

SUMO1‐conjugation is altered during normal aging but not by increased amyloid burden

“…Imbalances in protein homeostasis lead to the misfolding, aggregation and subsequent accumulation of various proteins into large deposits (Hartl, 2017). In the brain, the accumulation of misfolded proteins is part of a physiological process that leads to an age‐related decline in cognitive performance.…”

The Role of N‐Methyl Squaramides in a Hydrogen‐Bonding Strategy to Fold Peptidomimetic Compounds

“…[D 6 ]DMSO and CDCl 3 (99.8 %D) were stored on molecular sieves (3 ). 1 Ha nd 13 CNMR spectra were recorded at 600 and 300 MHz at 23 8Cu nless otherwise specified. Chemicals shifts are reported as parts per million (d)r eferenced to the residual deuterium lock solvents.…”

“…The secondary structures of proteins and peptides are crucial to their role in a broad array of fundamental biological processes. Protein misfolding is involved in the etiology of neurodegenerative disorders, including Parkinson, Alzheimer, and prionic diseases, among others . However, structural and conformational studies of proteins can be challenging because of their complexity and limited availability.…”

“…Protein misfolding is involved in the etiology of neurodegenerative disorders, including Parkinson, Alzheimer,a nd prionic diseases, among others. [1] However, structurala nd conformational studies of proteins can be challenging because of their complexity and limited availability.A sa na lternative, small-sized peptides are valuable andf ruitful modelst os tudy complex systemsb ecause they have simple architectures and are accessible by chemical synthesis. [2,3] Peptides are also natural candidates to developb ioactive compounds.…”

Self-Assembly of Open Protein Systems: A Comprehensive View Based onthe Interactions between 3d Hydrophobic and Electric Dipole MomentVectors

“…Nevertheless self-assembling processes have their own characteristics. For example, a conformational change in a protein may result in a pathological process of self-assembling impairing the protein in the performance of its original function [1][2][3].…”