SNCA – Lewy Body Dementia

Alpha-synuclein, encoded by SNCA, is a presynaptic protein whose aggregation in Lewy bodies is the neuropathological hallmark of Lewy body dementia (DLB). Heterozygous missense variants and copy number gains in SNCA cause autosomal dominant DLB.

The c.157G>A (p.Ala53Thr) variant was identified in a 41-year-old proband with levodopa-unresponsive parkinsonism progressing to dementia; three affected first-degree relatives harbored the same change and postmortem analysis revealed abundant Lewy neurites and Lewy bodies (PMID:15981014). An E46K mutation (c.136G>A (p.Glu46Lys)) segregated with parkinsonism, dementia, and sleep disturbances in seven members of a single family, demonstrating autosomal dominant inheritance of a DLB phenotype (PMID:16001411). The E83Q missense change (c.247G>C (p.Glu83Gln)) has been reported in a DLB patient and shown to markedly accelerate alpha-synuclein fibrillization, seeding activity, and formation of Lewy-body-like inclusions in neuronal models (PMID:35486726).

Inheritance is autosomal dominant with segregation of pathogenic SNCA variants in at least ten affected relatives across multiple pedigrees, including point mutations (A30P, A53T, E46K, E83Q) and SNCA multiplications.

Functional studies reveal that familial SNCA mutations accelerate in vitro fibril formation (A53T > A30P; PMID:9809558; PMID:10092675) and that transgenic mice expressing human A53T alpha-synuclein develop neurodegeneration with Lewy pathology (PMID:12084935). The E83Q variant further enhances aggregation kinetics, neuronal toxicity, and diversity of Lewy-body-like inclusions in seeding assays (PMID:35486726).

Mechanistically, SNCA variants confer a toxic gain-of-function via enhanced aggregation and fibril formation, leading to synaptic dysfunction and neuronal loss consistent with DLB pathology.

No studies have refuted the SNCA–DLB association; genetic and experimental data are concordant and comprehensive.

Key take-home: SNCA missense and multiplication variants are a definitive cause of autosomal dominant Lewy body dementia through accelerated alpha-synuclein aggregation, informing genetic diagnosis and therapeutic targeting.

References

• Acta neuropathologica • 2005 • Abundant neuritic inclusions and microvacuolar changes in a case of diffuse Lewy body disease with the A53T mutation in the alpha-synuclein gene. PMID:15981014
• Movement disorders • 2005 • Abnormal sleep architecture is an early feature in the E46K familial synucleinopathy. PMID:16001411
• Science advances • 2022 • A NAC domain mutation (E83Q) unlocks the pathogenicity of human alpha-synuclein and recapitulates its pathological diversity. PMID:35486726
• Nature medicine • 1998 • Accelerated in vitro fibril formation by a mutant alpha-synuclein linked to early-onset Parkinson disease. PMID:9809558
• The Journal of biological chemistry • 1999 • Both familial Parkinson's disease mutations accelerate alpha-synuclein aggregation. PMID:10092675
• Proceedings of the National Academy of Sciences of the United States of America • 2002 • Human alpha-synuclein-harboring familial Parkinson's disease-linked Ala-53 --> Thr mutation causes neurodegenerative disease with alpha-synuclein aggregation in transgenic mice. PMID:12084935

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