Protein Misfolding Dynamics in Neurodegenerative Disorders

Protein misfolding and its aberrant assembly into oligomers and fibrils lie at the heart of a range of age-related neurodegenerative disorders, including Alzheimer’s, Parkinson’s and Huntington’s diseases. Under physiological conditions, molecular chaperones and quality-control pathways guide nascent polypeptides towards their native conformations. In disease states, subtle perturbations of this balance lead to the accumulation of partially folded intermediates that adopt β-rich structures prone to self-association. The aggregation pathway is typically divided into a lag phase, during which nuclei form, a growth phase marked by rapid fibril elongation and a plateau phase when assembly reaches equilibrium. Secondary processes, such as surface-catalysed nucleation and fragmentation of existing fibrils, further accelerate deposition and diversification of polymorphic assemblies. Soluble oligomeric species are now recognised as particularly neurotoxic, disrupting cellular membranes, impairing synaptic function and triggering inflammatory cascades. The precise interplay between distinct aggregate forms and the progression of clinical symptoms remains an active area of investigation, with emerging evidence that structural polymorphism correlates with both regional vulnerability and rate of disease progression. Strategies aimed at stabilising native structures, preventing aberrant nucleation or promoting clearance of toxic species hold promise for therapeutic intervention.

Research from Nature Portfolio

One foundational study analysed patient-derived amyloid β-peptide fibrils by cryo-electron microscopy and revealed that in vivo assemblies adopt distinct polymorphic folds compared to those generated in vitro. This work underscored the importance of studying brain-isolated material to capture disease-relevant conformers and provided a structural rationale for strain-like behaviour in Alzheimer’s pathology. A complementary investigation employed infrared nanospectroscopy coupled with atomic force microscopy to track the conformational evolution of oligomeric and fibrillar species at the nanoscale. This approach uncovered an early α-to-β transition in intermediate assemblies and correlated mechanical stiffness with secondary structure, offering fresh insights into the molecular events that precede mature fibril formation.

Protein Misfolding Dynamics in Neurodegenerative Disorders publication trend

The graph below shows the total number of articles in protein misfolding dynamics in neurodegenerative disorders across all publications each year (not limited to Nature Index journals).

Technical terms

Protein misfolding: Failure of a polypeptide to attain its native three-dimensional structure, leading to aberrant interactions.

Amyloid fibril: A highly ordered, β-sheet-rich aggregate formed by proteins that self-assemble into unbranched fibres.

Oligomer: A small, soluble assembly of misfolded protein monomers, often implicated as the primary neurotoxic species.

Secondary nucleation: A process by which existing fibril surfaces catalyse the formation of new nuclei from soluble monomers.

Cryo-electron microscopy: A technique that images flash-frozen specimens at near-atomic resolution, preserving native structures.

Infrared nanospectroscopy: A method that combines atomic force microscopy with infrared absorption to probe molecular conformation at the nanoscale.

References

1. Cryo-EM structure and polymorphism of Aβ amyloid fibrils purified from Alzheimer’s brain tissue. Nature Communications (2019).
2. Infrared nanospectroscopy characterization of oligomeric and fibrillar aggregates during amyloid formation. Nature Communications (2015).
3. A closer look at amyloid ligands, and what they tell us about protein aggregates. Chemical Society Reviews (2024).
4. Structural evolution of fibril polymorphs during amyloid assembly. Cell (2023).
5. High-frequency terahertz waves disrupt Alzheimer’s β-amyloid fibril formation. eLight (2023).