tailieunhanh - Báo cáo khoa học: P25a ⁄ TPPP expression increases plasma membrane presentation of the dopamine transporter and enhances cellular sensitivity to dopamine toxicity

Parkinson’s disease is characterized by preferential degeneration of the dopamine-producing neurons of the brain stem substantia nigra. Imbal-ances between mechanisms governing dopamine transport across the plasma membrane and cellular storage vesicles increase the level of toxic pro-oxidative cytosolic dopamine. | IFEBS Journal P25a TPPP expression increases plasma membrane presentation of the dopamine transporter and enhances cellular sensitivity to dopamine toxicity Anja W. Fjorback1 2 Sabrina Sundbye2 Justus C. Dachsel2 f Steffen Sinning1 Ove Wiborg1 and Poul 1 Centre for Psychiatric Research Aarhus University Hospital Denmark 2 Department of MedicalBiochemistry Aarhus University Denmark Keywords dopamine transporter p25a Parkinsons disease toxicity TPPP tubulin polymerization promoting protein Correspondence . Jensen Department of Medical Biochemistry Aarhus University Ole Worms Alle 1170 DK-8000 Aarhus C Denmark Fax 45 86131160 Tel 45 89422856 E-mail phj@ Present address Stereology and EM Research Laboratory Aarhus University Denmark ỶPresent address Division of Neurogenetics Department of Neuroscience Mayo Clinic Florida Jacksonville FL 32224 USA Received 21 June 2010 revised 1 November 2010 accepted 20 November 2010 doi Parkinson s disease is characterized by preferential degeneration of the dopamine-producing neurons of the brain stem substantia nigra. Imbalances between mechanisms governing dopamine transport across the plasma membrane and cellular storage vesicles increase the level of toxic pro-oxidative cytosolic dopamine. The microtubule-stabilizing protein p25a accumulates in dopaminergic neurons in Parkinson s disease. We hypothesized that p25a modulates the subcellular localization of the dopamine transporter via effects on sorting vesicles and thereby indirectly affects its cellular activity. Here we show that co-expression of the dopamine transporter with p25a in HEK-293-MSR cells increases dopamine uptake via increased plasma membrane presentation of the transporter. No direct interaction between p25a and the dopamine transporter was demonstrated but they co-fractionated during subcellular fractionation of brain tissue from striatum and direct binding of p25a peptides to brain vesicles was .