α-Synuclein Fibrils Exhibit Gain of Toxic Function, Promoting Tau Aggregation and Inhibiting Microtubule Assembly

alpha-synuclein is the major component of Lewy bodies and Lewy neurites in Parkinson disease and dementia with Lewy bodies and of glial cytoplasmic inclusions in multiple system atrophy. It has been suggested that alpha-synuclein fibrils or intermediate protofibrils in the process of fibril formation may have a toxic effect on neuronal cells. In this study, we investigated the ability of soluble monomeric alpha-synuclein to promote microtubule assembly and the effects of conformational changes of alpha-synuclein on Tau -promoted microtubule assembly. In marked contrast to previous findings, monomeric alpha-synuclein had no effect on microtubule polymerization. However, both alpha-synuclein fibrils and protofibrils inhibited Tau-promoted micro tubule assembly. The inhibitory effect of alpha-synuclein fibrils was greater than that of the protofibrils. Dot blot overlay assay and spin -down techniques revealed that alpha-synuclein fibrils bind to Tau and inhibit microtubule assembly by depleting the Tau available for microtubule polymerization. Using various deletion mutants of a.-synuclein and Tau, the acidic C-terminal region of alpha-synuclein and the basic central region of Tau were identified as regions involved in the binding. Furthermore, introduction of alpha-synuclein fibrils into cultured cells overexpressing Tau protein induced Tau aggregation. These results raise the possibility that alpha-synuclein fibrils interact with Tau, inhibit its function to stabilize microtubules, and also promote Tau aggregation, leading to dysfunction of neuronal cells.