Alpha-synuclein fibrillar aggregates (α-syn fibrils)

Alpha-synuclein fibrillar aggregates are insoluble, beta-sheet rich protein structures that constitute the primary component of Lewy bodies and Lewy neurites (Spillantini et al., 1997, Nature). While monomeric alpha-synuclein is a soluble protein involved in synaptic vesicle trafficking and neurotransmitter release, its misfolding into fibrillar aggregates is a hallmark of synucleinopathies, including Parkinson's disease and Multiple System Atrophy (Goedert et al., 2017, Cold Spring Harb Perspect Med). These aggregates exert neurotoxicity by disrupting cellular membranes, impairing mitochondrial function, and overwhelming the proteasomal clearance system (Wong and Krainc, 2017, Nat Neurosci). Furthermore, alpha-synuclein fibrils exhibit prion-like properties, spreading from cell to cell and templating the misfolding of endogenous proteins (Luk et al., 2012, Science). Therapeutic development targeting these aggregates includes monoclonal antibodies like Prasinezumab designed to clear extracellular fibrils and small molecules like Anle138b intended to inhibit the aggregation process (Bender and Desplats, 2023, Biomolecules). Monitoring these aggregates via seed amplification assays (SAA) has become a critical tool for early diagnosis and clinical trial stratification (Concha-Marambio et al., 2023, Lancet Neurol).

Other names

Alpha-synuclein filamentsMisfolded alpha-synucleinPathogenic alpha-synucleinLewy body filamentsAmyloid-like alpha-synuclein

Inhibition of alpha-synuclein aggregation, promotion of fibril clearance via immunotherapy, and prevention of cell-to-cell propagation (seeding).