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.

Keywords: TDP-43; alpha synuclein; amyloid beta; intrinsic disorder; neurodegenerative disease; phase separation; prion protein; protein aggregation; tau.

Figure 1

Illustration of the energetic landscape of IDPs. Model of energetic landscape of intrinsically disordered proteins plotted as a function of free energy. Unstructured IDPs (in red) fluctuate among multiple structural states with slightly different values of free energy. Structural transition to lower free energy states involves the formation of β-enriched structures (in green). The process is reversible (gray arrows) and may depend on overlapping energetic levels. Interaction among β-structures leads to oligomers (purple). LLPS may achieved at this stage (blue line depicting the overall trend of the aggregation pathway).These structures may be on pathway for the transition to stable, solid aggregates, or may be off-pathway (depicted as wider holes) which are more stable and cannot proceed further in the path towards aggregation, but may revert back to their monomeric form (indicated by the grey arrows). The final stage of aggregation (blue) consists of solid aggregates such as fibrils, ribbons and amorphous aggregates, which represent the absolute minimum of free energy a protein can own.

Figure 2

Efficient autophagy is required to remove protein aggregates and prevent neurodegeneration. Vesicle nucleation is regulated by molecular components associated to mitochondria-associated endoplasmic reticulum (ER) membranes (MAM), some of which are enriched in the lipid raft of MAM, including gangliosides, AMBRA1 and ERLIN1. Autophagosome formation is necessary to prevent the accumulation of damaged proteins and to ensure cell survival. The alteration of the autophagic machinery during the early stages prevents the maturation of omegasomes by hindering the autophagic flux and the clearance of aggregated proteins, thus contributing to neurodegeneration.