Direct binding and functional coupling of alpha-synuclein to the dopamine transporters accelerate dopamine-induced apoptosis

FASEB J. 2001 Apr;15(6):916-26. doi: 10.1096/fj.00-0334com.


Mutations in alpha-synuclein, a protein highly enriched in presynaptic terminals, have been implicated in the expression of familial forms of Parkinson's disease (PD) whereas native alpha-synuclein is a major component of intraneuronal inclusion bodies characteristic of PD and other neurodegenerative disorders. Although overexpression of human alpha-synuclein induces dopaminergic nerve terminal degeneration, the molecular mechanism by which alpha-synuclein contributes to the degeneration of these pathways remains enigmatic. We report here that alpha-synuclein complexes with the presynaptic human dopamine transporter (hDAT) in both neurons and cotransfected cells through the direct binding of the non-A beta amyloid component of alpha-synuclein to the carboxyl-terminal tail of the hDAT. alpha-Synuclein--hDAT complex formation facilitates the membrane clustering of the DAT, thereby accelerating cellular dopamine uptake and dopamine-induced cellular apoptosis. Since the selective vulnerability of dopaminergic neurons in PD has been ascribed in part to oxidative stress as a result of the cellular overaccumulation of dopamine or dopamine-like molecules by the presynaptic DAT, these data provide mechanistic insight into the mode by which the activity of these two proteins may give rise to this process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cells, Cultured
  • Dopamine / pharmacology*
  • Dopamine Plasma Membrane Transport Proteins
  • Humans
  • Membrane Glycoproteins*
  • Membrane Transport Proteins*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurons / cytology
  • Neurons / metabolism*
  • Synucleins
  • Transfection
  • alpha-Synuclein


  • Carrier Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • SLC6A3 protein, human
  • SNCA protein, human
  • Synucleins
  • alpha-Synuclein
  • Dopamine