Cross-talk between α-synuclein and the microtubule cytoskeleton in neurodegeneration

Looking at the puzzle that depicts the molecular determinants in neurodegeneration, many pieces are lacking and multiple interconnections among key proteins and intracellular pathways still remain unclear. Here we focus on the concerted action of α-synuclein and the microtubule cytoskeleton, whose interplay, indeed, is emerging but remains largely unexplored in both its physiology and pathology. α-Synuclein is a key protein involved in neurodegeneration, underlying those diseases termed synucleinopathies. Its propensity to interact with other proteins and structures renders the identification of neuronal death trigger extremely difficult. Conversely, the unbalance of microtubule cytoskeleton in terms of structure, dynamics and function is emerging as a point of convergence in neurodegeneration. Interestingly, α-synuclein and microtubules have been shown to interact and mediate cross-talks with other intracellular structures. This is supported by an increasing amount of evidence ranging from their direct interaction to the engagement of in-common partners and culminating with their respective impact on microtubule-dependent neuronal functions. Last, but not least, it is becoming even more clear that α-synuclein and tubulin work synergically towards pathological aggregation, ultimately resulting in neurodegeneration. In this respect, we supply a novel perspective towards the understanding of α-synuclein biology and, most importantly, of the link between α-synuclein with microtubule cytoskeleton and its impact for neurodegeneration and future development of novel therapeutic strategies.