Neuropathology of synuclein aggregates: New insights into mechanisms of neurodegenerative diseases

Beginning with the isolation of the fragment of alpha-synuclein (alpha-syn) known as the non-A beta component of amyloid plaques (NAC peptide) from Al zheimer's disease (AD) brains, alpha-syn has been increasingly implicated i n the pathogenesis of neurodegenerative diseases, which now are classified as synucleinopathies. Indeed, unequivocal evidence linking abnormal alpha-s yn to mechanisms of brain degeneration came from discoveries of missense mu tations 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 patie nts with AD caused by genetic abnormalities demonstrated many a-syn positiv e LBs, Further, alpha-syn was implicated in the formation of the glial (GCl s) and neuronal cytoplasmic inclusions of multiple system atrophy, and the LBs, GCls and neuraxonal spheroids of neurodegeneration with brain iron acc umulation type I. Recently, two other members of the synuclein family, beta - and gamma-synuclein, have also been recognized to play a role in the path ogenesis of novel axonal lesions in PD and DLB. Evidence for a role of a-sy n in the formation of filamentous aggregates was reinforced by in vitro stu dies showing aggregation and fibrillogenesis of mutant and wild type alpha- syn. Indeed, since the aggregation of brain proteins into presumptively tox ic 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. (C) 2000 Wiley-Liss, Inc.