Synuclein Aggregation in Neurodegenerative Diseases

Synucleins are a family of small, intrinsically disordered proteins abundant at presynaptic terminals in vertebrate neurons. Among them, α-synuclein is central to the pathogenesis of Parkinson’s disease and related synucleinopathies by misfolding into β-sheet-rich oligomers and amyloid fibrils. Aggregation proceeds through nucleation-dependent pathways: initial misfolding events give rise to oligomeric intermediates that can seed further assembly, leading to fibrillar inclusions known as Lewy bodies. β-Synuclein and γ-synuclein share considerable sequence homology with α-synuclein but differ in their aggregation propensities. β-Synuclein can attenuate α-synuclein assembly by competing for lipid or fibril surfaces, whereas γ-synuclein generally resists fibrillation unless harbouring specific mutations. The spread of pathological synuclein species along anatomically connected regions suggests a prion-like mechanism and underlies progressive neuronal loss. Cellular factors such as lipid membranes, post-translational modifications and chaperone networks modulate aggregation kinetics and toxicity. The global health impact of synucleinopathies is profound, with no approved therapies that directly target aggregation. Understanding the molecular determinants of synuclein misfolding is therefore essential for developing disease-modifying interventions and biomarkers for early diagnosis.

Research from Nature Portfolio

Studies have revealed how β-synuclein can act as a natural inhibitor of α-synuclein assembly. Biophysical analyses demonstrate that β-synuclein binds competitively to lipid vesicles and the surfaces of α-synuclein fibrils, suppressing both the initiation of aggregation and secondary nucleation steps. This dual inhibition reduces the proliferation of toxic aggregates and suggests a therapeutic strategy based on mimicking β-synuclein interactions. Further work using nuclear magnetic resonance paramagnetic relaxation enhancement has elucidated the transient, low-affinity heterodimer between α- and β-synuclein. These head-to-tail interactions are specific and distinct from the less ordered self-interactions that drive α-synuclein aggregation. By defining the molecular surfaces and conformational dynamics that govern inhibition versus misfolding, these findings establish a framework for designing peptidic or small-molecule inhibitors that stabilise the inhibitory complex.

Synuclein Aggregation in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in synuclein aggregation in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

α-Synuclein: A 140-amino-acid presynaptic protein prone to misfolding into oligomers and amyloid fibrils implicated in Parkinson’s disease.

β-Synuclein: Homologous to α-synuclein but lacking key hydrophobic residues; acts as a natural inhibitor of α-synuclein aggregation.

Oligomer: A small assembly of misfolded monomeric proteins that can serve as intermediates in amyloid fibril formation and may be neurotoxic.

Secondary nucleation: A surface-catalysed process whereby existing fibrils accelerate the conversion of monomers into new aggregates, amplifying pathology.

Intrinsically disordered protein (IDP): A protein that lacks stable tertiary structure under physiological conditions but can adopt ordered conformations upon binding or aggregation.

References

1. Substitution of Met-38 to Ile in γ-synuclein found in two patients with amyotrophic lateral sclerosis induces aggregation into amyloid. Proceedings of the National Academy of Sciences of the United States of America (2024).
2. Interneuronal In Vivo Transfer of Synaptic Proteins. Cells (2023).
3. Alpha and Beta Synucleins: From Pathophysiology to Clinical Application as Biomarkers. Movement Disorders (2022).
4. β-Synuclein suppresses both the initiation and amplification steps of α-synuclein aggregation via competitive binding to surfaces. Scientific Reports (2016).
5. Parkinson's Disease-associated α-Synuclein Is More Fibrillogenic than β- and γ-Synuclein and Cannot Cross-seed Its Homologs*. Journal of Biological Chemistry (2000).
6. Unveiling transient protein-protein interactions that modulate inhibition of alpha-synuclein aggregation by beta-synuclein, a pre-synaptic protein that co-localizes with alpha-synuclein. Scientific Reports (2015).