Protein aggregation within the central nervous system has been recognized as a 
defining feature of neurodegenerative diseases since the early 20th century. 
Since that time, there has been a growing list of neurodegenerative disorders, 
including Parkinson disease, which are characterized by inclusions of specific 
pathogenic proteins. This has led to the long-held dogma that these 
characteristic protein inclusions, which are composed of large insoluble 
fibrillar protein aggregates and visible by light microscopy, are responsible 
for cell death in these diseases. However, the correlation between protein 
inclusion formation and cytotoxicity is inconsistent, suggesting that another 
form of the pathogenic proteins may be contributing to neurodegeneration. There 
is emerging evidence implicating soluble oligomers, smaller protein aggregates 
not detectable by conventional microscopy, as potential culprits in the 
pathogenesis of neurodegenerative diseases. The protein α-synuclein is well 
recognized to contribute to the pathogenesis of Parkinson disease and is the 
major component of Lewy bodies and Lewy neurites. However, α-synuclein also 
forms oligomeric species, with certain conformations being toxic to cells. The 
mechanisms by which these α-synuclein oligomers cause cell death are being 
actively investigated, as they may provide new strategies for diagnosis and 
treatment of Parkinson disease and related disorders. Here we review the 
possible role of α-synuclein oligomers in cell death in Parkinson disease and 
discuss the potential clinical implications.