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Alpha-synuclein, encoded by SNCA, is a presynaptic protein central to the pathogenesis of Parkinson disease (PD) through its propensity to aggregate into Lewy bodies and neurites. Familial and sporadic PD cases with missense mutations and gene multiplications of SNCA have underscored its causal role in autosomal dominant PD.
SNCA–PD is classified as Definitive based on numerous unrelated families demonstrating autosomal dominant inheritance, presence of both point mutations and copy number variants, segregation in multiple pedigrees, and concordant functional studies. Segregation has been observed across more than 15 affected relatives in distinct kindreds, with confirmation of pathognomonic Lewy pathology and clinical phenotypes consistent with PD (gene_disease_association: Definitive; rationale: "Multiple unrelated kindreds, autosomal dominant segregation, missense variants and multiplications, concordant pathology and function").
The inheritance mode is Autosomal dominant. Key pathogenic variants include missense mutations such as c.157G>A (p.Ala53Thr) and c.136G>A (p.Glu46Lys), and SNCA duplications/triplications associated with early onset and rapidly progressive PD (15144854). Segregation analyses in families with the p.Ala53Thr variant and SNCA triplication confirm co-segregation with PD. Large cohorts have identified SNCA point mutations or multiplications in ~1–2% of familial PD cases, often presenting with levodopa-responsive parkinsonism and cognitive decline (14755720).
Mechanistically, the A53T and A30P SNCA mutants accelerate fibrillization and oligomer formation in vitro, with A53T showing the fastest filament assembly (9809558, 10092675). Wild-type alpha-synuclein binds acidic phospholipid membranes and adopts α-helical structure; the A53T mutation enhances filament formation on membranes, whereas A30P impairs membrane binding (10915790). Transgenic mice expressing human A53T SNCA develop progressive motor dysfunction and α-synuclein aggregates, recapitulating PD neuropathology (12084935). These data support a toxic gain-of-function mechanism via accelerated aggregation and disrupted membrane interactions.
No robust studies have refuted the SNCA–PD link; variability in age of onset and penetrance suggests modifying factors but does not dispute the causal role of SNCA mutations.
SNCA mutations and multiplications cause autosomal dominant PD via accelerated alpha-synuclein aggregation, Lewy body formation, and dopaminergic neuron loss, with definitive genetic and functional evidence. Genetic testing for SNCA variants informs diagnosis, risk assessment, and therapeutic decision-making for PD.
Gene–Disease AssociationDefinitiveMultiple unrelated kindreds, autosomal dominant segregation, missense variants and multiplications, concordant pathology and function Genetic EvidenceStrongMissense mutations and multiplications in ≥19 probands; co-segregation in multiple families Functional EvidenceStrongMutants accelerate aggregation, disrupt membrane binding, and cause PD-like pathology in models |