DISSECTING THE INTERACTION OF a-SYNUCLEIN WITH TUBULIN/MICROTUBULES

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons and the accumulation and misfolding of α-synuclein. Remarkably, PD is even the fastest-growing neurological disorder; by 2040, the number of PD patients worldwide is expected to exceed 12 million. Despite tremendous scientific research and financial investments in PD, a cure for this devastating disorder remains elusive. Therefore, a better understanding of the biological mechanisms involved in PD is crucial for the discovery of disease-modifying therapies. Here, we focus on the interaction between α-synuclein and tubulin/microtubules and its potential role in neurodegeneration. Under physiological conditions, α-synuclein is proposed to function as a so-called microtubule dynamase, by interacting with tubulin α2β2 tetramer and promoting both microtubule growth rate and catastrophe frequency in vitro. However, the interaction of PD-associated α-synuclein mutations with tubulin, and its role in PD pathogenesis has not been fully elucidated yet. In this work, we report, for the first time, that tubulin directly interacts with various PD-related α-synuclein variants and diminishes tubulin polymerization in cell-free systems. Moreover, α- synuclein aggregation is reduced in the presence of purified tubulin, suggesting that tubulin could modulate α-synuclein pathology by inhibiting its aggregation through its interaction with α-synuclein. An advanced live-cell imaging approach in a cellular model demonstrated that α- synuclein does not impact microtubule dynamics in axon-like processes. Interestingly, the expression of α-synuclein-A53T, one of the most aggregation-prone PD-related α-synuclein mutations, reduced the velocity and processivity of APP-vesicle transport along microtubules in neuronally differentiated cells. Remarkably, we disclosed that treatment with an α-synuclein aggregation inhibitor can rescue these deficits in axonal transport, suggesting that α-synuclein inclusions impact vesicle transport. In addition, we present a novel α-synuclein aggregation inhibitor that effectively inhibits α-synuclein oligomeric species in cells, which could potentially function as a disease-modifying therapeutical drug in PD. To conclude, in this study we emphasize the importance of the α-synuclein/tubulin interaction, which directly or indirectly may play a major role in neurodegeneration.