Cofilin 1 activation prevents the defects in axon elongation and guidance induced by extracellular alpha-synuclein

Sci Rep. 2015 Nov 12:5:16524. doi: 10.1038/srep16524.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / metabolism
  • Animals
  • Axons / metabolism*
  • Cofilin 1 / genetics*
  • Cofilin 1 / metabolism*
  • Extracellular Space / metabolism
  • Humans
  • Mice
  • Mutation
  • Neurons / drug effects
  • Neurons / metabolism
  • Transcriptional Activation
  • Wound Healing
  • alpha-Synuclein / metabolism*
  • alpha-Synuclein / pharmacology

Substances

  • Actins
  • Cofilin 1
  • alpha-Synuclein