Alpha-synuclein (α-syn) aggregate (α-syn)

Alpha-synuclein is a 140-amino acid protein predominantly expressed in the brain, specifically within presynaptic terminals where it regulates synaptic vesicle dynamics and neurotransmitter release [1]. Under pathological conditions, the protein loses its native unfolded structure and misfolds into beta-sheet-rich soluble oligomers and insoluble fibrils [2]. These aggregated forms are the principal constituents of Lewy bodies and Lewy neurites, which are diagnostic markers for Parkinson's disease, Dementia with Lewy bodies, and Multiple system atrophy [3]. The aggregation process is thought to occur via a prion-like mechanism, where pathological seeds spread from neuron to neuron, leading to widespread neurodegeneration [4]. Therapeutic interventions targeting these aggregates include monoclonal antibodies designed to bind and clear extracellular alpha-synuclein, as well as small molecules that stabilize the monomeric form or inhibit the formation of toxic oligomers [5]. Current clinical research focuses on using these agents to modify the course of synucleinopathies by reducing the proteotoxic burden and preventing the spread of pathology throughout the nervous system [6]. Sources: [1] UniProt (P37840); [2] PubMed (PMID: 30635409); [3] NIH (NINDS); [4] PubMed (PMID: 23585022); [5] ClinicalTrials.gov (NCT03100149); [6] Nature Reviews Drug Discovery (doi:10.1038/d41573-022-00001-w).

Other names

Alpha-synuclein oligomerAlpha-synuclein fibrilSNCA aggregateLewy body proteinNon-amyloid component of plaques (NACP)

Therapeutic strategies involve monoclonal antibodies that selectively bind to aggregated alpha-synuclein to facilitate its clearance by microglia or neutralize extracellular seeds to prevent cell-to-cell transmission. Small molecule inhibitors are also employed to prevent the misfolding of monomers into toxic oligomers or to promote the disaggregation of existing fibrils.