Protein misfolding, aggregation, and conformational strains in neurodegenerative diseases

Abstract

A hallmark event in neurodegenerative diseases (NDs) is the misfolding, aggregation, and accumulation of proteins, leading to cellular dysfunction, loss of synaptic connections, and brain damage. Despite the involvement of distinct proteins in different NDs, the process of protein misfolding and aggregation is remarkably similar. A recent breakthrough in the field was the discovery that misfolded protein aggregates can self-propagate through seeding and spread the pathological abnormalities between cells and tissues in a manner akin to the behavior of infectious prions in prion diseases. This discovery has vast implications for understanding the mechanisms involved in the initiation and progression of NDs, as well as for the design of novel strategies for treatment and diagnosis. In this Review, we provide a critical discussion of the role of protein misfolding and aggregation in NDs. Commonalities and differences between distinct protein aggregates will be highlighted, in addition to evidence supporting the hypothesis that misfolded aggregates can be transmissible by the prion principle. We will also describe the molecular basis and implications for prion-like conformational strains, cross-interaction between different misfolded proteins in the brain, and how these concepts can be applied to the development of novel strategies for therapy and diagnosis.

Fig. 1 |. Protein aggregation and the prion principle of pathological transmission.

Monomeric proteins can misfold and aggregate. Spreading of protein misfolding operates at different levels during the pathogenesis of NDs, including molecule-to-molecule, cell-to-cell and brain region-to-brain region. In some specific cases, it may also operate to transmit the disease from individual to individual, as has been demonstrated for PrDs.

Fig. 2 |. Conformational strains and their implications for the spectrum of synucleinopathies and tauopathies.

Various NDs are associated with the accumulation of tau and α-Syn aggregates, which are referred as tauopathies and synucleinopathies. Recent evidence suggests that aggregates adopting different structures, illustrated here as schematics, may be responsible for these diseases.

Fig. 3 |. Cross-seeding interactions between diverse misfolded protein aggregates.

In vitro and in vivo experiments have shown that aggregates composed of one protein usually seed the aggregation of the same protein (homologous seeding). However, in some circumstances, an aggregate may also seed the aggregation of a different protein, in a process termed heterologous seeding or cross-seeding. Cross-seeding events may explain the frequent finding of mixed pathologies in which more than one misfolded protein aggregate is found in a patient brain.

Fig. 4 |. Therapeutic strategies targeting the prion-like spread of misfolded proteins.

The recognition of the prion principle in NDs provides several opportunities for therapeutic intervention at different levels of the protein misfolding cascade. This picture illustrates some of these targets using strategies that are currently under development.

Fig. 5 |. Disease diagnosis by sensitive detection of misfolded seeds in biological fluids.

The key role of misfolded protein oligomers in the prion-like spreading and neurodegeneration indicate that sensitive and specific detection of these structures in biological fluids might represent a good strategy for early biochemical diagnosis of NDs. Several strategies are under development for the detection of misfolded protein oligomers.