Alpha-synuclein A53T mutant messenger RNA (SNCA A53T mRNA)

Alpha-synuclein A53T mutant messenger RNA (mRNA) is the transcript of the SNCA gene carrying a specific missense mutation (G209A) that results in an alanine-to-threonine substitution at position 53 of the protein. This mutation is a well-established cause of early-onset, autosomal dominant familial Parkinson's disease and is characterized by the accelerated misfolding and aggregation of alpha-synuclein into toxic oligomers and insoluble fibrils. These aggregates are the primary components of Lewy bodies, which drive neurodegeneration in the substantia nigra. Therapeutic strategies targeting this mRNA aim to reduce the production of the toxic mutant protein using nucleic acid-based modalities such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs). Experimental small molecules like Synucleozid-2.0 and Syn-RiboTAC have also been developed to bind the structured 5' UTR of the mRNA to inhibit translation or induce targeted degradation. A critical focus of current research is allele-specific silencing, which seeks to selectively degrade the mutant transcript while preserving the wild-type mRNA to maintain essential physiological functions such as synaptic vesicle trafficking and neurotransmitter release. However, therapeutic development faces challenges regarding the safety of long-term alpha-synuclein knockdown and the efficient delivery of drugs across the blood-brain barrier.

Other names

SNCA A53T mRNAAlpha-synuclein A53T transcriptPARK1 A53T mRNAG209A SNCA mRNAAlpha-synuclein A53T mutant mRNA

RNA interference (RNAi), RNase H-mediated degradation, Translation inhibition, Targeted RNA degradation (RIBOTAC)