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Parkinson's disease genetic mutations increase cell susceptibility to stress: mutant alpha-synuclein enhances H2O2- and Sin-1-induced cell death.
Neurobiol Aging. 2007 Nov; 28(11):1709-17.NA

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. Alpha-synuclein is a major component of Lewy bodies in sporadic PD, and genetic alterations in alpha-synuclein cause autosomal-dominant hereditary PD. The pathogenesis of PD remains incompletely understood, but it appears to involve both genetic susceptibility and environmental factors. Here we investigated the effect of alpha-synuclein expression on cell susceptibility to proteasome inhibition, oxidative and nitrative stresses by using a PC 12-Tet-off regulatory system. We found that inducible expression of A30P or A53T mutant alpha-synuclein decreased the proteasome activity, increased intracellular ROS levels, and enhanced lactacystin- and H2O2-induced cell death. Furthermore, 3-nitrotyrosine levels increased in cells expressing alpha-synuclein, and further increased after Sin-1 (a NO donor) treatment compared with untreated or treated non-induced cells. Expression of alpha-synuclein (mutant more than wild type) significantly enhances Sin-1 toxicity. These results indicate that genetic mutations in alpha-synuclein may increase neuronal vulnerability to cellular stress in aging and PD pathogenesis.

Authors+Show Affiliations

Jiang H
Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Wu YC
No affiliation info available
Nakamura M
No affiliation info available
Liang Y
No affiliation info available
Tanaka Y
No affiliation info available
Holmes S
No affiliation info available
Dawson VL
No affiliation info available
Dawson TM
No affiliation info available
Ross CA
No affiliation info available
Smith WW
No affiliation info available

MeSH

AnimalsCell DeathDose-Response Relationship, DrugGenetic Predisposition to DiseaseHydrogen PeroxideMolsidomineMutationPC12 CellsParkinson DiseaseRatsReactive Oxygen Speciesalpha-Synuclein

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16978743

Citation

Jiang, Haibing, et al. "Parkinson's Disease Genetic Mutations Increase Cell Susceptibility to Stress: Mutant Alpha-synuclein Enhances H2O2- and Sin-1-induced Cell Death." Neurobiology of Aging, vol. 28, no. 11, 2007, pp. 1709-17.
Jiang H, Wu YC, Nakamura M, et al. Parkinson's disease genetic mutations increase cell susceptibility to stress: mutant alpha-synuclein enhances H2O2- and Sin-1-induced cell death. Neurobiol Aging. 2007;28(11):1709-17.
Jiang, H., Wu, Y. C., Nakamura, M., Liang, Y., Tanaka, Y., Holmes, S., Dawson, V. L., Dawson, T. M., Ross, C. A., & Smith, W. W. (2007). Parkinson's disease genetic mutations increase cell susceptibility to stress: mutant alpha-synuclein enhances H2O2- and Sin-1-induced cell death. Neurobiology of Aging, 28(11), 1709-17.
Jiang H, et al. Parkinson's Disease Genetic Mutations Increase Cell Susceptibility to Stress: Mutant Alpha-synuclein Enhances H2O2- and Sin-1-induced Cell Death. Neurobiol Aging. 2007;28(11):1709-17. PubMed PMID: 16978743.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Parkinson's disease genetic mutations increase cell susceptibility to stress: mutant alpha-synuclein enhances H2O2- and Sin-1-induced cell death. AU - Jiang,Haibing, AU - Wu,Yen-Ching, AU - Nakamura,Masayuki, AU - Liang,Yideng, AU - Tanaka,Yuji, AU - Holmes,Susan, AU - Dawson,Valina L, AU - Dawson,Ted M, AU - Ross,Christopher A, AU - Smith,Wanli W, Y1 - 2006/09/15/ PY - 2006/04/11/received PY - 2006/07/25/revised PY - 2006/07/28/accepted PY - 2006/9/19/pubmed PY - 2007/12/6/medline PY - 2006/9/19/entrez SP - 1709 EP - 17 JF - Neurobiology of aging JO - Neurobiol Aging VL - 28 IS - 11 N2 - Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. Alpha-synuclein is a major component of Lewy bodies in sporadic PD, and genetic alterations in alpha-synuclein cause autosomal-dominant hereditary PD. The pathogenesis of PD remains incompletely understood, but it appears to involve both genetic susceptibility and environmental factors. Here we investigated the effect of alpha-synuclein expression on cell susceptibility to proteasome inhibition, oxidative and nitrative stresses by using a PC 12-Tet-off regulatory system. We found that inducible expression of A30P or A53T mutant alpha-synuclein decreased the proteasome activity, increased intracellular ROS levels, and enhanced lactacystin- and H2O2-induced cell death. Furthermore, 3-nitrotyrosine levels increased in cells expressing alpha-synuclein, and further increased after Sin-1 (a NO donor) treatment compared with untreated or treated non-induced cells. Expression of alpha-synuclein (mutant more than wild type) significantly enhances Sin-1 toxicity. These results indicate that genetic mutations in alpha-synuclein may increase neuronal vulnerability to cellular stress in aging and PD pathogenesis. SN - 1558-1497 UR - https://www.unboundmedicine.com/medline/citation/16978743/Parkinson's_disease_genetic_mutations_increase_cell_susceptibility_to_stress:_mutant_alpha_synuclein_enhances_H2O2__and_Sin_1_induced_cell_death_ DB - PRIME DP - Unbound Medicine ER -