Protein Aggregation Landscape in Neurodegenerative Diseases: Clinical Relevance and Future Applications

Abstract

Intrinsic disorder is a natural feature of polypeptide chains, resulting in the lack of a defined three-dimensional structure. Conformational changes in intrinsically disordered regions of a protein lead to unstable β-sheet enriched intermediates, which are stabilized by intermolecular interactions with other β-sheet enriched molecules, producing stable proteinaceous aggregates. Upon misfolding, several pathways may be undertaken depending on the composition of the amino acidic string and the surrounding environment, leading to different structures. Accumulating evidence is suggesting that the conformational state of a protein may initiate signalling pathways involved both in pathology and physiology. In this review, we will summarize the heterogeneity of structures that are produced from intrinsically disordered protein domains and highlight the routes that lead to the formation of physiological liquid droplets as well as pathogenic aggregates. The most common proteins found in aggregates in neurodegenerative diseases and their structural variability will be addressed. We will further evaluate the clinical relevance and future applications of the study of the structural heterogeneity of protein aggregates, which may aid the understanding of the phenotypic diversity observed in neurodegenerative disorders.

Insight into membraneless organelles and their associated proteins: Drivers, Clients and Regulators

“…LLPS is a tightly regulated process, which when perturbed, can undergo a transition from a physiological liquid condensate to pathological solid-like protein aggregates, leading to aging-associated diseases [6] , [82] and various neurodegenerative pathologies, among which Alzheimer, Parkinson, Huntington, ALS and FTD diseases stand out [2] , [18] , [68] , [100] . In this work we focus on the nine most representative MLOs comprising at least 15 associated proteins.…”

SARS-CoV-2 Invasion and Pathological Links to Prion Disease

“…All known PrDs are progressive, transmissible, have no known effective treatment or cure, are always fatal, and are characterized by the insidious onset of neurological deficits, which are caused in part by the accumulation and aggregation of a misfolded prion protein ‘scrapie’ isoform (PrP sc ) derived from a native cellular prion protein (PrP c ). The rapid development of a progressive systemic inflammation and protein aggregation is very similar in its presentation to Alzheimer’s disease (AD) and other protein-mis-folding disorders such as the tauopathies [ 20 , 21 , 41 , 42 , 43 , 50 ].…”

Pseudogenes and Liquid Phase Separation in Epigenetic Expression

“…Recent study has revealed that LLPS is regulated by intrinsically disordered proteins (IDPs). These misfolded proteins lack a proper 3D structure, which help them to form membrane-less organelles (56,57). The alpha-synuclein and beta-amyloid are common misfolded proteins in liquid phase aggregate formation (57).…”

“…These misfolded proteins lack a proper 3D structure, which help them to form membrane-less organelles (56,57). The alpha-synuclein and beta-amyloid are common misfolded proteins in liquid phase aggregate formation (57). As science evolves, a recent study shows that pseudogenes influence the LLPS by mediating the aggregation of these misfolded proteins.…”