• J E Duda, V M Lee, and J Q Trojanowski.
• Center For Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
• J. Neurosci. Res. 2000 Jul 15;61(2):121-7.

AbstractBeginning 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.Copyright 2000 Wiley-Liss, Inc.

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