Impairment Of Pdgf-Induced Chemotaxis By Extracellular Alpha-Synuclein Through Selective Inhibition Of Rac1 Activation

Parkinson's disease (PD) is characterized by alpha-synuclein (a-Syn)-positive intracytoplasmic inclusions, known as Lewy bodies. Although it is known that extracellular a-Syn is detected in the plasma and cerebrospinal fluid, its physiological significance remains unclear. Here, we show that extracellular alpha-Syn suppresses platelet-derived growth factor (PDGF)-induced chemotaxis in human neuroblastoma SH-SY5Y cells. The inhibitory effect was stronger in the mutant alpha-Syn(A53T), found in hereditary PD, and the degree of inhibition was time-dependent, presumably because of the oligomerization of a-Syn. PDGF-induced activation of Akt or Erk was not influenced by alpha-Syn(A53T). Further studies revealed that alpha-Syn(A53T) inhibited PDGF-induced Rac1 activation, whereas Cdc42 activation remained unaffected, resulting in unbalanced actin filament remodeling. These results shed light on the understanding of pathological as well as physiological functions of extracellular a-Syn in neuronal cells.