Alpha-synuclein (A53T) (SNCA (A53T))

Alpha-synuclein is a 140-amino acid protein primarily localized in the presynaptic terminals of neurons, where it plays a critical role in regulating synaptic vesicle trafficking and the release of neurotransmitters such as dopamine (UniProt: P37840). The A53T mutation, involving a substitution of alanine with threonine at position 53, was the first genetic mutation identified as a cause of familial Parkinson's disease and is known to significantly accelerate the protein's tendency to misfold and aggregate (PubMed: 9204901). These aggregates form toxic oligomers and insoluble fibrils that are the primary components of Lewy bodies, the pathological hallmark of synucleinopathies (PubMed: 10446552). Targeting the gene expression of the A53T variant, particularly through the use of antisense oligonucleotides (ASOs) or RNA interference, aims to reduce the total cellular burden of the pathogenic protein to halt or slow neurodegeneration (ClinicalTrials.gov: NCT03708224). Current therapeutic development focuses on lowering SNCA mRNA levels, inhibiting protein-protein interactions that lead to aggregation, and enhancing the clearance of existing aggregates to preserve neuronal integrity.

Other names

SNCA A53TPARK1PARK4Non-amyloid component of plaque precursorNACPAlpha-synuclein gene expression

Antisense oligonucleotides (ASOs) bind to SNCA mRNA to induce RNase H-mediated degradation, reducing the translation of the alpha-synuclein protein; small molecules inhibit the aggregation of monomers into toxic oligomers and fibrils; monoclonal antibodies target and neutralize extracellular alpha-synuclein to prevent cell-to-cell spread.