Pathogenic alpha-synuclein aggregates (alpha-syn aggregates)

Pathogenic alpha-synuclein aggregates are the defining pathological feature of synucleinopathies, a category of neurodegenerative diseases that includes Parkinson's disease, Dementia with Lewy bodies, and Multiple system atrophy (UniProt P37840). In these conditions, the normally soluble alpha-synuclein protein undergoes a conformational shift into beta-sheet-rich oligomers and insoluble fibrils, which accumulate as Lewy bodies (PubMed 30244349). These aggregates exert neurotoxicity by disrupting mitochondrial respiration, lysosomal function, and synaptic vesicle recycling, ultimately leading to dopaminergic neuronal loss. A critical aspect of their pathology is the prion-like ability to spread between neurons, templating the misfolding of endogenous alpha-synuclein in a progressive manner (PubMed 35105774). Therapeutic interventions currently in clinical development include immunotherapies like Prasinezumab and small molecules like Anle138b, which aim to reduce aggregate burden or prevent their propagation. Monitoring these aggregates has been revolutionized by the development of seed amplification assays (SAA), which allow for high-sensitivity detection in cerebrospinal fluid (PubMed 37116524).

Other names

Alpha-synuclein fibrilsAlpha-synuclein oligomersMisfolded alpha-synucleinLewy bodiesLewy neuritesPhosphorylated alpha-synucleinpS129 alpha-synuclein

Therapeutic strategies include monoclonal antibodies that bind to and clear extracellular aggregates to prevent cell-to-cell spreading, small molecules that inhibit the nucleation and elongation of toxic oligomers or fibrils, and agents that enhance the degradation of existing aggregates via the autophagy-lysosome pathway.