Tubulin Seeds α-Synuclein Fibril Formation

Abstract

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...

Parkinsonian Neurotoxin 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and α-Synuclein Mutations Promote Tau Protein Phosphorylation at Ser262 and Destabilize Microtubule Cytoskeleton in Vitro

“…Previous studies have shown that tubulin co-localizes with ␣-synuclein in Lewy bodies and ␣-synuclein positive pathological structures (55). In vitro, tubulin promotes ␣-synuclein fibrillization, and ␣-synuclein was reported to directly interact with microtubules in vitro (55).…”

“…In vitro, tubulin promotes ␣-synuclein fibrillization, and ␣-synuclein was reported to directly interact with microtubules in vitro (55). When neurons were exposed to fibrillar ␣-synuclein, it caused microtubule depolymerization (54).…”

Prolyl Oligopeptidase Enhances α-Synuclein Dimerization via Direct Protein-Protein Interaction

“…The N-terminal and central NAC domains of aSyn interact with lipids in cellular membranes and with some proteins (41)(42)(43)(44), whereas the C-terminal domain was shown to bind metal ions (38). aSyn interactions with proteins, such as synphilin-1 (45) and tubulin (46), small molecules, and macromolecules, such as dopamine (47), polysaccharides (48), and metal ions (11) can enhance aggregation of aSyn. Because the aggregation process is nucleation-dependent (12,49,50), it is possible that some of these interaction partners function as a seeding point for aSyn oligomerization and aggregation.…”

Microtubule Depolymerization Suppresses α-Synuclein Accumulation in a Mouse Model of Multiple System Atrophy

“…Although the physiological role of the interaction between ␣-syn and ␤-tubulin is not completely clear, previous reports showed that ␣-syn interacted with heterodimeric tubulin 28 and that tubulin initiated and promoted ␣-syn fibril formation under physiological conditions in vitro. 29 Indeed, in the MSA Tg mice, once the insoluble complex was formed, microtubule depolymerization agent was ineffective in blocking of the ␣-syn accumulation. However, microtubule depolymerization agent suppressed the accumulation of insoluble ␣-syn complex before the neuronal ␣-syn expression was developed by the oligodendrocytes overexpressing human ␣-syn.…”