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Differential effects of overexpression of wild-type and mutant human alpha-synuclein on MPP+-induced neurotoxicity in PC12 cells.
Neurosci Lett. 2008 Apr 18; 435(2):142-6.NL

Abstract

The genetic background and the pathogenesis of familial Parkinson's disease (PD) have not been fully elucidated. Two missense mutations in the alpha-synuclein gene, A30P and A53T, have been linked to familial PD. Increasing evidence suggests the involvement of alpha-synuclein, the dopamine transporter (DAT), and neurotoxins in the pathogenesis of PD, but their relationships to the death of nigral cells remains poorly understood. In the present study, we used the PC12 cell line, a well recognized model of the nigral cell, to investigate the effects of overexpression of wild-type (WT) and mutant human alpha-synuclein on MPP+-induced neurotoxicity. We found that overexpression of mutant alpha-synuclein enhanced the toxicity of MPP+ to PC12 cells and elevated intracellular reactive oxygen species (ROS) levels, whereas overexpression of WT alpha-synuclein protected PC12 cells against MPP+ toxicity and lowered ROS levels. Furthermore, assays of 131I-FP-beta-CIT binding with DAT membrane fractions showed that WT and mutant alpha-synuclein had different effects on the expression of DAT on the cell membrane following exposure to MPP+. WT alpha-synuclein reduced the toxic effect of MPP+ by facilitating DAT internalization, while both A30P and A53T alpha-synuclein aggravated the toxic effect of MPP+ by reducing DAT internalization. These data indicate that alpha-synuclein regulates ROS levels and DAT surface expression in dopaminergic neurons, and thus changes the response of these cells to MPP+.

Authors+Show Affiliations

Department of Neurology, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou 215004, China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

18342443

Citation

Qian, Jin-Jun, et al. "Differential Effects of Overexpression of Wild-type and Mutant Human Alpha-synuclein On MPP+-induced Neurotoxicity in PC12 Cells." Neuroscience Letters, vol. 435, no. 2, 2008, pp. 142-6.
Qian JJ, Cheng YB, Yang YP, et al. Differential effects of overexpression of wild-type and mutant human alpha-synuclein on MPP+-induced neurotoxicity in PC12 cells. Neurosci Lett. 2008;435(2):142-6.
Qian, J. J., Cheng, Y. B., Yang, Y. P., Mao, C. J., Qin, Z. H., Li, K., & Liu, C. F. (2008). Differential effects of overexpression of wild-type and mutant human alpha-synuclein on MPP+-induced neurotoxicity in PC12 cells. Neuroscience Letters, 435(2), 142-6. https://doi.org/10.1016/j.neulet.2008.02.021
Qian JJ, et al. Differential Effects of Overexpression of Wild-type and Mutant Human Alpha-synuclein On MPP+-induced Neurotoxicity in PC12 Cells. Neurosci Lett. 2008 Apr 18;435(2):142-6. PubMed PMID: 18342443.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Differential effects of overexpression of wild-type and mutant human alpha-synuclein on MPP+-induced neurotoxicity in PC12 cells. AU - Qian,Jin-Jun, AU - Cheng,Yan-Bo, AU - Yang,Ya-Ping, AU - Mao,Cheng-Jie, AU - Qin,Zheng-Hong, AU - Li,Kai, AU - Liu,Chun-Feng, Y1 - 2008/02/16/ PY - 2007/12/13/received PY - 2008/02/03/revised PY - 2008/02/12/accepted PY - 2008/3/18/pubmed PY - 2008/7/31/medline PY - 2008/3/18/entrez SP - 142 EP - 6 JF - Neuroscience letters JO - Neurosci Lett VL - 435 IS - 2 N2 - The genetic background and the pathogenesis of familial Parkinson's disease (PD) have not been fully elucidated. Two missense mutations in the alpha-synuclein gene, A30P and A53T, have been linked to familial PD. Increasing evidence suggests the involvement of alpha-synuclein, the dopamine transporter (DAT), and neurotoxins in the pathogenesis of PD, but their relationships to the death of nigral cells remains poorly understood. In the present study, we used the PC12 cell line, a well recognized model of the nigral cell, to investigate the effects of overexpression of wild-type (WT) and mutant human alpha-synuclein on MPP+-induced neurotoxicity. We found that overexpression of mutant alpha-synuclein enhanced the toxicity of MPP+ to PC12 cells and elevated intracellular reactive oxygen species (ROS) levels, whereas overexpression of WT alpha-synuclein protected PC12 cells against MPP+ toxicity and lowered ROS levels. Furthermore, assays of 131I-FP-beta-CIT binding with DAT membrane fractions showed that WT and mutant alpha-synuclein had different effects on the expression of DAT on the cell membrane following exposure to MPP+. WT alpha-synuclein reduced the toxic effect of MPP+ by facilitating DAT internalization, while both A30P and A53T alpha-synuclein aggravated the toxic effect of MPP+ by reducing DAT internalization. These data indicate that alpha-synuclein regulates ROS levels and DAT surface expression in dopaminergic neurons, and thus changes the response of these cells to MPP+. SN - 0304-3940 UR - https://www.unboundmedicine.com/medline/citation/18342443/Differential_effects_of_overexpression_of_wild_type_and_mutant_human_alpha_synuclein_on_MPP+_induced_neurotoxicity_in_PC12_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0304-3940(08)00203-6 DB - PRIME DP - Unbound Medicine ER -