Increasing evidence suggests that ␣-synuclein is a common pathogenic molecule in several neurodegenerative diseases, particularly in Parkinson's disease. To understand ␣-synuclein pathology, we investigated molecules that interact with ␣-synuclein in human and rat brains and identified tubulin as an ␣-synuclein binding-/associated protein. Tubulin co-localized with ␣-synuclein in Lewy bodies and other ␣-synuclein-positive pathological structures. Tubulin initiated and promoted ␣-synuclein fibril formation under physiological conditions in vitro. These findings suggest that an interaction between tubulin and ␣-synuclein might accelerate ␣-synuclein aggregation in diseased brains, leading to the formation of Lewy bodies. The non-␤-amyloid (A␤)1 component of Alzheimer's disease amyloid, or NAC, originally detected in an amyloid-enriched fraction, was shown to be a fragment of its precursor, NACP, by cloning of the full-length cDNA (1). Later, NACP turned out to be a human homologue of Torpedo synuclein (2). Therefore, it is also referred to as human ␣-synuclein (3). ␣-Synuclein is abundant in presynaptic terminals of neurons (4). Recently, two missense mutations in the ␣-synuclein gene (5) were discovered in certain pedigrees with familial Parkinson's disease and were shown to segregate with the illness (6, 7). Shortly thereafter, ␣-synuclein was identified as the major filamentous component of Lewy bodies (LBs) in Parkinson's disease (8, 9) and of cytoplasmic inclusions in multiple system atrophy (MSA) (10 -12).Thus, ␣-synuclein appears to be a common pathogenic molecule in these diseases.Although the physiological role of ␣-synuclein is unknown, ␣-synuclein has the property of forming fibrils by itself in vitro, and mutations of ␣-synuclein accelerate the fibril formation (13,14). However, the vast majority of cases of neurodegenerative diseases associated with LBs or with ␣-synuclein pathology, such as Parkinson's disease, dementia with Lewy bodies (DLB), MSA, and the LB variant of Alzheimer's disease, are sporadic, where wild-type ␣-synuclein has shown to be abnormally accumulated as fibrillar structures. It is therefore likely that at some stage(s) in the fibril formation of ␣-synuclein, either the nucleation and/or the elongation steps should be somehow accelerated in diseased brains, or alternatively, some degradation process(es) of abnormal structures of ␣-synuclein might be defective in those patients (15).With respect to the amyloidogenesis of Alzheimer's disease, it was demonstrated in vitro that a seed of NAC can accelerate A␤ fibril formation, and conversely, a seed of A␤ can promote NAC fibril formation (16). Similarly, heterogeneous molecules could also be involved in the formation of ␣-synuclein fibrils, leading to pathological structures of ␣-synuclein such as LBs.In this study, we performed a biochemical investigation of molecules that interact with ␣-synuclein in the human brain, and we identified tubulin as one of the ␣-synuclein binding/ associated proteins. This interaction was confirmed by co...