The Aggregation Continuum of α-Synuclein and Its Relevance to Brain Aging

α-Synuclein aggregation in synucleinopathies involves abnormal accumulation of α-synuclein protein in neurons. This aggregation process generates oligomers, protofibrils, and fibrils, disrupting cellular function and contributing to the progression of neurodegeneration observed in Parkinson’s disease, multiple system atrophy, and dementia with Lewy bodies. Typically, these aggregates range in size from tens to hundreds of nanometers to a few micrometers. The intermediate-sized aggregation species, so-called oligomers, have been implicated in the neurotoxicity observed in Parkinson’s disease. Small-sized, soluble oligomers exhibit pore formation in lipid bilayers, impair synaptic transmission, and induce oxidative stress, ultimately leading to neuronal dysfunction. This review explores the size-dependent toxicity of α-synuclein aggregates, focusing on how variations in aggregate size influence their pathological effects in neurodegenerative diseases. It discusses the diverse structural forms of α-synuclein, including monomers, oligomers, protofibrils, and large-sized fibrils, and their differential impact on cellular function and viability. By elucidating the size-dependent mechanisms underlying α-synuclein toxicity, this review aims to inform therapeutic strategies targeting specific aggregate sizes to mitigate neuronal damage and halt Parkinson’s disease progression.