Propagation Mechanisms of Alpha-Synuclein in Neurodegenerative Diseases

Alpha-synuclein misfolding and aggregation underpin a spectrum of neurodegenerative disorders, notably Parkinson’s disease, Lewy body dementia and multiple system atrophy. Pathological species of alpha-synuclein propagate through prion-like mechanisms, whereby aberrant protein conformers seed further misfolding and spread between cells via extracellular vesicles, direct trans-synaptic transfer and unconventional secretion. Membrane receptors, endolysosomal processing and autophagic pathways are critical determinants of uptake, trafficking and release of pathological aggregates. Recent advances have elucidated molecular interactions that govern these processes, offering potential targets to arrest the cell-to-cell dissemination of alpha-synuclein and to mitigate disease progression.

Research from Nature Portfolio

Recent studies have identified amyloid β precursor-like protein 1 as a critical co-receptor with lymphocyte-activation gene 3, which together facilitate the binding, internalisation and neurotoxicity of preformed alpha-synuclein fibrils, and showed that disrupting this interaction prevents dopaminergic cell loss in vivo. Foundational work has characterised discrete prefibrillar oligomeric assemblies of alpha-synuclein, revealing that stable elongated oligomers seed aggregation within cells, albeit less efficiently than mature fibrils, thereby clarifying the spectrum of species that contribute to intercellular propagation.

Propagation Mechanisms of Alpha-Synuclein in Neurodegenerative Diseases publication trend

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

Technical terms

Alpha-synuclein: A presynaptic neuronal protein prone to misfolding into pathological aggregates found in Lewy bodies and neurites.

Prion-like spreading: A mechanism by which misfolded proteins act as templates to induce misfolding of native counterparts and propagate between cells.

Preformed fibrils (PFF): Laboratory-generated aggregates of alpha-synuclein used to model seeding and transmission in cellular and animal studies.

Oligomer: A soluble, intermediate assembly of alpha-synuclein that may seed aggregation and contribute to toxicity.

Autophagy: A cellular degradation pathway mediating the clearance of protein aggregates via autophagosome formation and lysosomal fusion.

References

1. Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions. Molecular Neurodegeneration (2025).
2. Aplp1 interacts with Lag3 to facilitate transmission of pathologic α-synuclein. Nature Communications (2024).
3. Artificial intelligence-driven drug repositioning uncovers efavirenz as a modulator of α-synuclein propagation: Implications in Parkinson’s disease. Biomedicine & Pharmacotherapy (2024).
4. Structural and functional properties of prefibrillar α-synuclein oligomers. Scientific Reports (2016).