α-Synuclein is a major constituent of pathological intracellular inclusion bodies, a common feature of several neurodegenerative diseases. Two missense mutations in the α-synuclein gene have been identified in confirmed autosomal-dominant familial Parkinson's disease, which segregate with the illness. However, the physiological function of α-synuclein remains unknown. After biochemical investigations we have revealed tubulin to be an α-synuclein associated/binding protein. Here, we show that α-synuclein induces polymerization of purified tubulin into microtubules. Mutant forms of α-synuclein lose this potential. The binding site of α-synuclein to tubulin is identified, and co-localization of α-synuclein with microtubules is shown in cultured cells. To our knowledge, this is the first demonstration of microtubule-polymerizing activity of α-synuclein. Now we can see a striking resemblance between α-synuclein and tau: both have the same physiological function and pathological features, making abnormal structures in diseased brains known as synucleinopathies and tauopathies. The discovery of a physiological role for α-synuclein may provide a new dimension in researches into the mechanisms of α-synuclein-associated neurodegenerative diseases.

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...

We examined neuronal cytoplasmic inclusions (NCIs) and oligodendrocytic glial cytoplasmic inclusions (GCIs) in the pontine nuclei in multiple system atrophy (MSA) using antibodies against the non-amyloid beta component of Alzheimer's disease amyloid precursor protein (NACP/alpha-synuclein). Our immunohistochemical study revealed that anti-NACP antibodies labeled both NCIs and GCIs. Immunoelectron microscopy showed that positive reaction products were localized on the 15- to 30-nm-thick filamentous components of NCIs and GCIs. The present study demonstrates that NACP is associated with cytoplasmic inclusions of MSA, and suggests a role of NACP in abnormal filament aggregation in neuronal degeneration.

Antioxidants have been proposed to have antiatherogenic potential by their inhibition of low density lipoprotein (LDL) oxidation. Here, we report an antioxidant, BO-653 (2,3-dihydro-5-hydroxy-2,2-dipentyl-4,6-di-tert-butylbenzofuran), designed to exhibit antioxidative potency comparable to that of ␣-tocopherol, but yet possess a high degree of lipophilicity comparable to that of probucol. BO-653 exhibits a high affinity for LDL and is well distributed in aortic vessels in vivo. In atherosclerosis models of rabbits and mice, BO-653 has been shown to be able to suppress the formation of atherosclerotic lesions without untoward side effects. Specifically, there was no reduction of high density lipoprotein levels. This antioxidant provides additional evidence in support of the oxidized-LDL hypothesis, and itself is a promising candidate antioxidant for clinical use.