Lewy body / α-synuclein

Lewy bodies are eosinophilic intraneuronal inclusions composed predominantly of aggregated α-synuclein protein, first described by Friedrich Lewy in 1912 and identified as the defining pathological feature of Parkinson's disease, dementia with Lewy bodies (DLB), and Parkinson's disease dementia. α-Synuclein (encoded by SNCA) is a presynaptic protein involved in dopaminergic vesicle trafficking; under conditions that include genetic mutations or multiplications of SNCA, oxidative stress, impaired autophagy and lysosomal dysfunction, it misfolds and self-assembles into oligomers and then amyloid-like fibrils that propagate between neurons in a prion-like fashion consistent with Braak's staging of Parkinson's pathology. Whether α-synuclein aggregation is the primary driver of neurodegeneration or a consequence of upstream cellular failure is debated, though the discovery of SNCA multiplications causing familial Parkinson's and the toxicity of oligomeric species in cellular models favour a causal role. In DLB — the second most common neurodegenerative dementia — Lewy body pathology produces fluctuating cognition, visual hallucinations, REM sleep behaviour disorder and parkinsonism, often in combination with Alzheimer co-pathology.