title: Cofilin 1 activation prevents the defects in axon elongation and guidance induced by extracellular alpha-synuclein.
abstract: Impaired adult neurogenesis and axon traumatic injury participate in the severity of neurodegenerative diseases. Alpha-synuclein, a cytosolic protein involved in Parkinson's disease, may be released from neurons, suggesting a role for excess secreted alpha-synuclein in the onset and spread of the pathology. Here we provide evidence that long term exposure of young neurons to extracellular alpha-synuclein hampers axon elongation and growth cone turning. We show that actin turnover and the rate of movement of actin waves along the axon are altered, due to alpha-synuclein-induced inactivation of cofilin. Upon laser disruption of microfilaments, healing of axons is favored by the increased phosphorylation of cofilin, however, at later time points; the defect in neurite extension prevails, being lost the regulation of cofilin activity. Importantly, overexpression of the active form of cofilin in neurons exposed to alpha-synuclein is able to restore the movement of actin waves, physiological axon elongation and growth cone turning. Our study reveals the molecular basis of alpha-synuclein-driven deficits in growth and migration of newborn neurons, and in elongation and regeneration of adult neurons.
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
authors.forename: Sharada
authors.initials: S
authors.lastname: Tilve
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Difato
authors.affiliation: Department of Neuroscience and Brain Technologies, Istituto Italiano di Tecnologia, 16163 Genoa, Italy.
authors.forename: Evelina
authors.initials: E
authors.lastname: Chieregatti
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001369:Axons / Q000378:metabolism*; D051338:Cofilin 1 / Q000235:genetics* / Q000378:metabolism*; D005110:Extracellular Space / Q000378:metabolism; D006801:Humans; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation; D014945:Wound Healing; D051844:alpha-Synuclein / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000199:Actins; D051338:Cofilin 1; D051844:alpha-Synuclein