Modulation of dopamine transporter function by α-synuclein is altered by impairment of cell adhesion and by induction of oxidative stress Export

@article{citeulike:4067975, abstract = {Human -synuclein accumulates in dopaminergic neurons as intraneuronal inclusions, Lewy bodies, which are characteristic of idiopathic Parkinson's disease (PD). Here, we suggest that modulation of the functional activity of the dopamine transporter (DAT) by -synuclein may be a key factor in the preferential degeneration of mesencephalic dopamine (DA)-synthesizing neurons in PD. In cotransfected Ltk-, HEK 293, and SK-N-MC cells, -synuclein induced a 35\% decrease in [3H]DA uptake. Biotinylated DAT levels were decreased by 40\% in cotransfected cells relative to cells expressing only DAT. DAT was colocalized with -synuclein in mesencephalic neurons and cotransfected Ltk- cells. Coimmunoprecipitation studies showed the existence of a complex between -synuclein and DAT, in specific rat brain regions and cotransfected cells, through specific amino acid motifs of both proteins. The attenuation of DAT function by -synuclein was cytoprotective, because DA-mediated oxidative stress and cell death were reduced in cotransfected cells. The neurotoxin MPP+ (1-methyl-4-phenylpyridinium), oxidative stress, or impairment of cell adhesion ablated the -synuclein-mediated inhibition of DAT activity, which caused increased uptake of DA and increased biotinylated DAT levels, in both mesencephalic neurons and cotransfected cells. These studies suggest a novel normative role for -synuclein in regulating DA synaptic availability and homeostasis, which is relevant to the pathophysiology of PD. Key words: Parkinson's disease synucleinopathies MPP+ neurodegeneration Lewy bodies 10.1096/fj.03-0152fje}, author = {Wersinger, Christophe and Prou, Delphine and Vernier, Philippe and Sidhu, Anita}, citeulike-article-id = {4067975}, citeulike-linkout-0 = {http://dx.doi.org/10.1096/fj.03-0152fje}, citeulike-linkout-1 = {http://view.ncbi.nlm.nih.gov/pubmed/12958153}, citeulike-linkout-2 = {http://www.hubmed.org/display.cgi?uids=12958153}, day = {4}, doi = {10.1096/fj.03-0152fje}, journal = {FASEB J.}, keywords = {a-synuclein, cell\_adhesion, dopamine\_transporter, oxidative\_stress}, month = {September}, pages = {03-0152fje+}, posted-at = {2009-02-18 17:33:04}, priority = {3}, title = {Modulation of dopamine transporter function by \α-synuclein is altered by impairment of cell adhesion and by induction of oxidative stress}, url = {http://dx.doi.org/10.1096/fj.03-0152fje}, year = {2003} }

TY - JOUR ID - citeulike:4067975 L3 - citeulike-article-id:4067975 N2 - Human -synuclein accumulates in dopaminergic neurons as intraneuronal inclusions, Lewy bodies, which are characteristic of idiopathic Parkinson's disease (PD). Here, we suggest that modulation of the functional activity of the dopamine transporter (DAT) by -synuclein may be a key factor in the preferential degeneration of mesencephalic dopamine (DA)-synthesizing neurons in PD. In cotransfected Ltk-, HEK 293, and SK-N-MC cells, -synuclein induced a 35% decrease in [3H]DA uptake. Biotinylated DAT levels were decreased by 40% in cotransfected cells relative to cells expressing only DAT. DAT was colocalized with -synuclein in mesencephalic neurons and cotransfected Ltk- cells. Coimmunoprecipitation studies showed the existence of a complex between -synuclein and DAT, in specific rat brain regions and cotransfected cells, through specific amino acid motifs of both proteins. The attenuation of DAT function by -synuclein was cytoprotective, because DA-mediated oxidative stress and cell death were reduced in cotransfected cells. The neurotoxin MPP+ (1-methyl-4-phenylpyridinium), oxidative stress, or impairment of cell adhesion ablated the -synuclein-mediated inhibition of DAT activity, which caused increased uptake of DA and increased biotinylated DAT levels, in both mesencephalic neurons and cotransfected cells. These studies suggest a novel normative role for -synuclein in regulating DA synaptic availability and homeostasis, which is relevant to the pathophysiology of PD. Key words: Parkinson's disease synucleinopathies MPP+ neurodegeneration Lewy bodies 10.1096/fj.03-0152fje JF - FASEB J. TI - Modulation of dopamine transporter function by α-synuclein is altered by impairment of cell adhesion and by induction of oxidative stress SP - 03-0152fje KW - a-synuclein KW - cell_adhesion KW - dopamine_transporter KW - oxidative_stress AU - Wersinger, Christophe AU - Prou, Delphine AU - Vernier, Philippe AU - Sidhu, Anita PY - 2003/09/04/ UR - http://dx.doi.org/10.1096/fj.03-0152fje ER -