Binding of neuronal α-synuclein to β-III tubulin and accumulation in a model of multiple system atrophy

α-Synuclein Oligomers Impair Neuronal Microtubule-Kinesin Interplay

“…Thus, our data provide evidence that ␣-Syn seeds might be the species that evoke MT dysfunction and destabilize MT networks under ␣-Syn-aggregating conditions. Interestingly, tubulin has been shown to promote ␣-Syn fibril formation, to form insoluble complexes with ␣-Syn in primary mouse neurons, and to colocalize with ␣-Syn in Lewy bodies (16,20,21). In turn, ␣-Syn seeds induce depolymerization of MTs and thereby increase the level of free tubulin.…”

β-III Tubulin Fragments Inhibit α-Synuclein Accumulation in Models of Multiple System Atrophy

“…Furthermore, ingestion of nocodazole attenuated impaired synaptic function in MSA mice (13). Although the antibiotic rifampicin, which inhibits ␣-syn self-aggregation, decreased recombinant ␣-syn aggregation in vitro, it had little effect on the aggregation of ␣-syn in primary cultured neurons derived from MSA mice (16). These results strongly suggest that free ␤-III tubulin binds to ␣-syn and then polymerizes to form microtubules.…”

“…It was also reported that ␣-syn binds to monomeric tubulin and stimulates microtubule polymerization (24). Indeed, blocking tubulin polymerization using nocodazole resulted in reduced ␣-syn accumulation (12,16). Furthermore, ingestion of nocodazole attenuated impaired synaptic function in MSA mice (13).…”

“…Furthermore, we demonstrated that accumulation of insoluble ␣-syn was suppressed by a microtubule-depolymerizing agent, indicating that free ␤-III tubulin-␣-syn molecules are less prone to inclusion formation (12,16). Although the binding of neuronal ␣-syn to ␤-III tubulin is a key pathogenic process in the MSA mouse model, it is still unclear whether and how ␣-syn binds to ␤-III tubulin in patients with MSA.…”

Animal Models of Multiple-System Atrophy

“…However, the CNP-aSyn model was valuable to address protein interactions, suggesting that the presence of oligodendroglial human aSyn may lead to the accumulation of endogenous mouse aSyn and trigger axonal degeneration. Furthermore, beta-III tubulin was identified as an important interaction partner of aSyn, which may participate in the neuronal aggregate formation in MSA [23,24]. Recent observations in the CNP-aSyn transgenic mouse suggested that the neuronal, pre-synaptic accumulation of aSyn may induce synaptic dysfunction of GABAergic interneurons [25].…”