Beginning with the isolation of the fragment of
alpha-synuclein (alpha-syn) known as the non-Abeta component of
amyloid plaques (NAC
peptide) from
Alzheimer's disease (AD) brains, alpha-syn has been increasingly implicated in the pathogenesis of
neurodegenerative diseases, which now are classified as
synucleinopathies. Indeed, unequivocal evidence linking abnormal alpha-syn to mechanisms of brain degeneration came from discoveries of missense mutations in the alpha-syn gene pathogenic for familial
Parkinson's disease (PD) in rare kindreds. Shortly thereafter, alpha-syn was shown to be a major component of Lewy bodies (LBs) and Lewy neurites in sporadic PD,
dementia with LBs (DLB) and the LB variant of AD. Also, studies of brains from patients with AD caused by genetic abnormalities demonstrated many alpha-syn positive LBs. Further, alpha-syn was implicated in the formation of the glial (GCIs) and neuronal cytoplasmic inclusions of
multiple system atrophy, and the LBs, GCIs and neuraxonal spheroids of
neurodegeneration with brain iron accumulation type 1. Recently, two other members of the
synuclein family, beta- and
gamma-synuclein, have also been recognized to play a role in the pathogenesis of novel axonal lesions in PD and DLB. Evidence for a role of alpha-syn in the formation of filamentous aggregates was reinforced by in vitro studies showing aggregation and fibrillogenesis of mutant and wild type alpha-syn. Indeed, since the aggregation of brain
proteins into presumptively toxic lesions is emerging as a common but poorly understood mechanistic theme in sporadic and
hereditary neurodegenerative diseases, clarification of the mechanism of
synuclein aggregation could augment efforts to develop novel and more effective
therapies for many
neurodegenerative disorders.