title: α-Synuclein is a Novel Microtubule Dynamase.
abstract: α-Synuclein is a presynaptic protein associated to Parkinson's disease, which is unstructured when free in the cytoplasm and adopts α helical conformation when bound to vesicles. After decades of intense studies, α-Synuclein physiology is still difficult to clear up due to its interaction with multiple partners and its involvement in a pletora of neuronal functions. Here, we looked at the remarkably neglected interplay between α-Synuclein and microtubules, which potentially impacts on synaptic functionality. In order to identify the mechanisms underlying these actions, we investigated the interaction between purified α-Synuclein and tubulin. We demonstrated that α-Synuclein binds to microtubules and tubulin α2β2 tetramer; the latter interaction inducing the formation of helical segment(s) in the α-Synuclein polypeptide. This structural change seems to enable α-Synuclein to promote microtubule nucleation and to enhance microtubule growth rate and catastrophe frequency, both in vitro and in cell. We also showed that Parkinson's disease-linked α-Synuclein variants do not undergo tubulin-induced folding and cause tubulin aggregation rather than polymerization. Our data enable us to propose α-Synuclein as a novel, foldable, microtubule-dynamase, which influences microtubule organisation through its binding to tubulin and its regulating effects on microtubule nucleation and dynamics.
authors.affiliation: Dept. Biosciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Daniele
authors.initials: D
authors.lastname: Cartelli
authors.affiliation: Dept. Biosciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aliverti
authors.affiliation: Dept. of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Barbiroli
authors.affiliation: Dept. Biotecnology and Biosciences, Università degli Studi di Milano-Bicocca, Milano, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Santambrogio
authors.affiliation: Dept. of Food, Environmental and Nutritional Sciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Enzio M
authors.initials: EM
authors.lastname: Ragg
authors.affiliation: Dept. Biosciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Francesca V M
authors.initials: FV
authors.lastname: Casagrande
authors.affiliation: Dept. Biosciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cantele
authors.affiliation: Dept. Biosciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Beltramone
authors.affiliation: Dept. Biosciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Marangon
authors.affiliation: Dept. Biosciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Carmelita
authors.initials: C
authors.lastname: De Gregorio
authors.affiliation: Dept. Biosciences, Università degli Studi di Milano, Milano, Italy.
authors.forename: Vittorio
authors.initials: V
authors.lastname: Pandini
authors.affiliation: Dept. Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Emanuele
authors.affiliation: Dept. Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, Genova, Italy.
authors.forename: Evelina
authors.initials: E
authors.lastname: Chieregatti
authors.affiliation: Dept. Chemistry, Università degli Studi di Milano, Milano, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Pieraccini
authors.affiliation: Stem Cell laboratory for CNS Disease Modeling, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden.|Strategic Research Area MultiPark and Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: Staffan
authors.initials: S
authors.lastname: Holmqvist
authors.affiliation: Dept. Biology, University of Padova, Padova, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Bubacco
authors.affiliation: Stem Cell laboratory for CNS Disease Modeling, Wallenberg Neuroscience Center, Department of Experimental Medical Science, Lund University, Lund, Sweden.|Strategic Research Area MultiPark and Lund Stem Cell Center, Lund University, Lund, Sweden.
authors.forename: Laurent
authors.initials: L
authors.lastname: Roybon
authors.affiliation: Parkinson Institute, ASST G. Pini-CTO, ex ICP, Milano, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Pezzoli
authors.affiliation: Dept. Biotecnology and Biosciences, Università degli Studi di Milano-Bicocca, Milano, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Grandori
authors.affiliation: Grenoble Institut des Neurosciences, Grenoble, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Arnal
authors.affiliation: Dept. Biosciences, Università degli Studi di Milano, Milano, Italy.|Center of Excellence on Neurodegenerative Diseases, Università degli Studi di Milano, Milano, Italy.
authors.forename: Graziella
authors.initials: G
authors.lastname: Cappelletti
mesh_terms: D006801:Humans; D008870:Microtubules / Q000737:chemistry / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000235:genetics*; D011485:Protein Binding; D017510:Protein Folding; D055503:Protein Multimerization / Q000235:genetics; D014404:Tubulin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D014404:Tubulin; D051844:alpha-Synuclein