Phosphorylation Mechanisms in Alpha-Synucleinopathies

Alpha-synucleinopathies, including Parkinson’s disease and multiple system atrophy, are characterised by the abnormal accumulation of α-synuclein aggregates in neuronal and glial cells. Phosphorylation, a reversible post-translational modification, modulates α-synuclein’s conformation, aggregation propensity and interaction with cellular partners. In healthy neurons, low levels of serine-129 phosphorylation regulate synaptic vesicle dynamics and protein–protein interactions in an activity-dependent manner. Dysregulation of kinases such as Polo-like kinase 2 and phosphatases like protein phosphatase 2A leads to hyperphosphorylation at serine-129, promoting the formation of protease-resistant aggregates within Lewy bodies. Recent findings reveal that phosphorylated α-synuclein adopts distinct structural strains with enhanced seeding capacity and cytotoxicity, and that artificial protein modulators can reverse aberrant phosphorylation to restore synaptic function. The interplay between neuronal activity, calcium-dependent signalling pathways and the balance of kinase/phosphatase activity underpins both physiological roles and pathological accumulation of phosphorylated α-synuclein. Understanding these mechanisms offers insights into selective cellular vulnerability and potential strategies to modulate post-translational modifications for therapeutic benefit.

Research from Nature Portfolio

Artificial protein modulators modelled on phosphatases have been engineered to target hyperphosphorylated α-synuclein directly. These de novo catalysts hydrolyse phosphate groups from serine-129 in vitro and in cellular models, reducing aggregation and rescuing synaptic deficits in Parkinsonian systems. In parallel, studies of phosphorylated α-synuclein fibrils demonstrate that serine-129 modification accelerates neuronal uptake of preformed fibrils, enhances aggregation in the substantia nigra and precipitates dopaminergic cell loss and motor impairment. Phosphorylated fibrils also modulate innate immune responses, altering macrophage recruitment and cytokine release. Together these works establish phosphorylation at serine-129 not only as a marker of pathology but as an active driver of strain diversity, propagation efficiency and neuroinflammation.

Phosphorylation Mechanisms in Alpha-Synucleinopathies publication trend

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

Technical terms

Phosphorylation: Covalent attachment of a phosphate group to amino acid residues, modulating protein function.

Alpha-synuclein: Neuronal protein implicated in synucleinopathies, capable of forming amyloid aggregates.

Serine-129 phosphorylation (pS129): Addition of phosphate at residue 129 of α-synuclein, central to aggregation and pathology.

Kinase: Enzyme transferring phosphate groups to proteins.

Phosphatase: Enzyme removing phosphate groups from proteins.

Post-translational modification (PTM): Chemical alteration of proteins after synthesis, affecting their properties.

Lewy bodies: Intracellular inclusions rich in aggregated, phosphorylated α-synuclein.

Artificial protein modulator (APROM): Engineered catalyst mimicking phosphatase activity to dephosphorylate target proteins.

References

1. An artificial protein modulator reprogramming neuronal protein functions. Nature Communications (2024).
2. Serine-129 phosphorylation of α-synuclein is an activity-dependent trigger for physiologic protein-protein interactions and synaptic function. Neuron (2023).
3. Dynamic physiological α-synuclein S129 phosphorylation is driven by neuronal activity. npj Parkinson's Disease (2023).
4. Alpha-synuclein aggregates are phosphatase resistant. Acta Neuropathologica Communications (2024).
5. Impact of Phosphorylation on the Physiological Form of Human alpha-Synuclein in Aqueous Solution. Journal of Chemical Information and Modeling (2024).
6. Phosphorylated exogenous alpha-synuclein fibrils exacerbate pathology and induce neuronal dysfunction in mice. Scientific Reports (2017).
7. Phosphorylation induces distinct alpha-synuclein strain formation. Scientific Reports (2016).