Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Abstract

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aβ, tau), α-synuclein, IAPP and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D) and amyotrophic lateral sclerosis (ALS) research, respectively for over many years.While SOD1 is a globular protein with a well-defined 3D structure, the Aβ, tau and α-synuclein proteins belong to the class of intrinsically disordered proteins (IDPs). IDPs are also known to play a critical role in many cellular functions such as signal transduction, cell growth, binding with DNA and RNA, and transcription, and are implicated in the development of cardiovascular problems and cancers 29 . The IDPs involved in neurodegenerative diseases have a few aggregation-prone regions and overall all IDPs have a low mean hydrophobicity and a high mean net charge 30 .IDPs are structurally flexible and lack stable secondary structures in aqueous solution. When isolated, they behave as polymers in a good solvent and their radii of gyration are well described by the Flory scaling law. 31 The insolubility and high self-assembly propensity of IDPs implicated in degenerative diseases have prevented high-resolution structural determination by solution nuclear magnetic resolution (NMR) and X-ray diffraction experiments. Local information at all aggregation steps can be, however, obtained by chemical shifts, residual coupling constants, and J-couplings from NMR, exchange hydrogen/deuterium (H/D) NMR, Raman spectroscopy; and secondary structure from fast Fourier infrared spectroscopy (FTIR) or circular dichroism (CD). Long-range tertiary contacts can be deduced from paramagnetic relaxation enhancement (PRE) NMR spectroscopy and single molecule Förster resonance energy transfer (sm-FRET), and short-range distance contacts can be extracted by cross linked residues determined by mass spectrometry (MS). Low-resolution 3D information of monomers and oligomers can be obtained by ion-mobility mass-spectrometry data (IM/MS) providing cross-collision sections, dynamic light scattering (DLS), pulse field gradient NMR spectroscopy and fluorescence correlation spectroscopy (FCS) providing hydrodynamics radius, small-angle X-ray scattering (SAXS) and small-angle neutron scattering (SANS), atomic force microscopy (AFM) and transmission electron microscopy (TEM) providing height features of the aggregates, as reported by some o...

Effect of Surface Roughness on Aggregation of Polypeptide Chains: A Monte Carlo Study

“…The self-assembly of proteins into aggregates of various morphologies is probably one of the main causes of chronic neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's disease [1][2][3]. Therefore, understanding the mechanisms of protein aggregation plays an important role in discovering effective therapies to treat these diseases.…”

From System Modeling to System Analysis: The Impact of Resolution Level and Resolution Distribution in the Computer-Aided Investigation of Biomolecules

“…As no unique parametrization strategy exists, a plethora of atomistic force fields have been developed through the years, all having a strikingly similar functional form but different coefficients. In the case of proteins, examples of common atomistic force fields are Amber ( Maier et al, 2015 ) and CHARMM ( Huang and MacKerell, 2013 ); recently, improved versions of these force fields for both folded and intrinsically disordered proteins have also been developed ( Huang et al, 2017 ; Robustelli et al, 2018 ), in addition to force field types designed for amyloid assembly ( Nguyen et al, 2021 ). In any of these force fields, each amino acid type in a defined protonation state is described through the same set of parameters, irrespective of its position along the protein sequence; exceptions are the N- and C-termini, which usually require ad hoc parameterisations according to the capping groups.…”

“…In 1975, Levitt and Warshel published a paper in which they employed an extremely crude representation of a protein in terms of few sites endowed with simple interactions to gain insight in the process of protein folding ( Levitt and Warshel, 1975 ); while the specific results obtained have been later questioned ( Hagler and Honig, 1978 ), this work represents a milestone as the first, pioneering attempt to investigate fundamental biophysical problems making use of minimalistic models of the system instead of extremely accurate ones. Since then, biomolecular CG modeling has steadily grown to become an essential tool in the computational investigation of biological matter: only considering proteins, a whole zoo of CG models and techniques has been developed, which aim at capturing the physicochemical behavior of a large variety of molecules over a wide range of characteristic length and time scales ( Saunders and Voth, 2012 ; Kmiecik et al, 2016 ; Singh and Li, 2019 ; Nguyen et al, 2021 ). Given this extreme diversity, we deem it useful to briefly recapitulate the main concepts underlying the development or choice of a CG model.…”

Liquid–liquid phase separation of Tau by self and complex coacervation

“…The nature of this intrinsic disorder paired with a highly charged amino acid composition offers ample opportunity for Tau molecules to engage in multivalent molecular interactions with itself and many other biomolecular constituents within the cell. Adverse conditions, by mechanisms not well understood, can lead to the self‐assembly and subsequent fibrillization of Tau into a cross β‐sheet structure, 1,2 a hallmark of Alzheimer's neurofibrillary tangles 3,4 . Tau has been mainly characterized as a microtubule binding protein, with most of the protein localized to the axons of neurons.…”

“…This makes the advent of intracellular aggregation of Tau more puzzling as it necessarily requires higher local Tau concentration than the basal level in the normal cellular state. It is in this context that the emergence of Tau liquid–liquid phase separation (LLPS) into sub‐cellular scale condensates has received enormous interest and generated new hypotheses in the research community of Tau biology 4,8,13,24–31 . It is an active debate whether LLPS promotes or protects from, or is not directly connected to pathological aggregation of Tau.…”