Pathological alpha-synuclein aggregates (α-syn aggregates)

Pathological alpha-synuclein aggregates are the primary constituents of Lewy bodies and Lewy neurites, which serve as the definitive pathological hallmarks of Parkinson's disease and other synucleinopathies (PubMed: 33571414). While the native, monomeric form of alpha-synuclein is a soluble protein involved in regulating synaptic vesicle trafficking and neurotransmitter release, its transition into misfolded oligomers and insoluble fibrils leads to profound neurotoxicity (UniProt: P37840). These pathological aggregates disrupt cellular membranes, impair mitochondrial respiration, and overwhelm the protein degradation machinery, including the ubiquitin-proteasome system and autophagy-lysosomal pathways (PubMed: 29351583). A defining characteristic of these aggregates is their prion-like ability to template the misfolding of endogenous alpha-synuclein, facilitating the spread of pathology across interconnected brain regions. Current drug development efforts focus on reducing the burden of these toxic species through immunotherapy, which targets extracellular aggregates for clearance, or small molecules designed to stabilize the monomeric state and inhibit the initial stages of aggregation (PubMed: 35145244). Monitoring these aggregates has been revolutionized by seed amplification assays, which allow for the detection of misfolded alpha-synuclein in cerebrospinal fluid with high sensitivity and specificity (PubMed: 37163011).

Other names

Alpha-synuclein oligomersAlpha-synuclein fibrilsLewy body filamentsSNCA aggregatesProtofibrilsMisfolded alpha-synuclein

Therapeutic approaches include passive immunization using monoclonal antibodies to neutralize and clear extracellular aggregates, small molecule inhibitors to prevent the misfolding and aggregation of monomers, and antisense oligonucleotides (ASOs) to reduce the overall expression of the SNCA gene (PubMed: 35145244).