N6-methyladenosine (m6A) hypermethylation of SNCA mRNA in substantia nigra dopaminergic neurons stabilises the transcript, increases alpha-synuclein protein levels, and lowers the concentration threshold for protein aggregation into Lewy bodies. Pharmacological inhibition of METTL3 (the primary m6A writer) should reduce SNCA mRNA stability, lower alpha-synuclein protein levels, and decrease aggregation in PD model neurons.
Curated pathway from expert analysis
flowchart TD
A["METTL3 m6A Writer Complex<br/>Substantia Nigra Dopaminergic Neurons"]
B["N6-Methyladenosine Hypermethylation<br/>SNCA mRNA Specific Sites"]
C["SNCA Transcript Stabilized<br/>Reduced mRNA Turnover Rate"]
D["Alpha-Synuclein Protein Levels Rise<br/>Above Aggregation Threshold"]
E["Lewy Body Nucleation<br/>Lower Critical Concentration"]
F["Lewy Body Pathology Progression<br/>Dopaminergic Neuron Loss"]
G["Parkinson Disease Neurodegeneration"]
H["METTL3 Pharmacological Inhibition<br/>SNCA mRNA Destabilization Strategy"]
A --> B
B --> C
C --> D
D --> E
E --> F
F --> G
H -.->|"reduce SNCA levels"| B
style B fill:#7b1fa2,stroke:#ce93d8,color:#ce93d8
style G fill:#b71c1c,stroke:#ef9a9a,color:#ef9a9a
style H fill:#1b5e20,stroke:#a5d6a7,color:#a5d6a7No linked papers recorded for this hypothesis yet.
No clinical trials data linked to this hypothesis yet.
No curated ClinVar variants loaded for this hypothesis.
Run scripts/backfill_clinvar_variants.py to fetch P/LP/VUS variants.
No DepMap CRISPR Chronos data found for SNCA.
Run python3 scripts/backfill_hypothesis_depmap.py to populate.