Dieldrin Induces Ubiquitin-Proteasome Dysfunction in α-Synuclein Overexpressing Dopaminergic Neuronal Cells and Enhances Susceptibility to Apoptotic Cell Death
| العنوان: | Dieldrin Induces Ubiquitin-Proteasome Dysfunction in α-Synuclein Overexpressing Dopaminergic Neuronal Cells and Enhances Susceptibility to Apoptotic Cell Death |
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| المؤلفون: | Calivarathan Latchoumycandane, Faneng Sun, Anumantha G. Kanthasamy, Arthi Kanthasamy, Vellareddy Anantharam |
| المصدر: | Journal of Pharmacology and Experimental Therapeutics. 315:69-79 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2005. |
| سنة النشر: | 2005 |
| مصطلحات موضوعية: | Insecticides, Proteasome Endopeptidase Complex, Programmed cell death, Dopamine, Apoptosis, DNA Fragmentation, Cell Line, Dieldrin, chemistry.chemical_compound, Parkinsonian Disorders, Ubiquitin, Phagosomes, Dopaminergic Cell, Animals, Caspase, Neurons, Pharmacology, Dose-Response Relationship, Drug, biology, Caspase 3, Environmental exposure, Molecular biology, Rats, nervous system diseases, Oxidative Stress, chemistry, Cell culture, Caspases, biology.protein, Molecular Medicine |
| الوصف: | Exposure to pesticides is implicated in the etiopathogenesis of Parkinson's disease (PD). The organochlorine pesticide dieldrin is one of the environmental chemicals potentially linked to PD. Because recent evidence indicates that abnormal accumulation and aggregation of alpha-synuclein and ubiquitin-proteasome system dysfunction can contribute to the degenerative processes of PD, in the present study we examined whether the environmental pesticide dieldrin impairs proteasomal function and subsequently promotes apoptotic cell death in rat mesencephalic dopaminergic neuronal cells overexpressing human alpha-synuclein. Overexpression of wild-type alpha-synuclein significantly reduced the proteasomal activity. Dieldrin exposure dose-dependently (0-70 microM) decreased proteasomal activity, and 30 microM dieldrin inhibited activity by more than 60% in alpha-synuclein cells. Confocal microscopic analysis of dieldrin-treated alpha-synuclein cells revealed that alpha-synuclein-positive protein aggregates colocalized with ubiquitin protein. Further characterization of the aggregates with the autophagosomal marker mondansyl cadaverine and the lysosomal marker and dot-blot analysis revealed that these protein oligomeric aggregates were distinct from autophagosomes and lysosomes. The dieldrin-induced proteasomal dysfunction in alpha-synuclein cells was also confirmed by significant accumulation of ubiquitin protein conjugates in the detergent-insoluble fraction. We found that proteasomal inhibition preceded cell death after dieldrin treatment and that alpha-synuclein cells were more sensitive than vector cells to the toxicity. Furthermore, measurement of caspase-3 and DNA fragmentation confirmed the enhanced sensitivity of alpha-synuclein cells to dieldrin-induced apoptosis. Together, our results suggest that increased expression of alpha-synuclein predisposes dopaminergic cells to proteasomal dysfunction, which can be further exacerbated by environmental exposure to certain neurotoxic compounds, such as dieldrin. |
| تدمد: | 1521-0103 0022-3565 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::5ee44755abba114035dc208edea62e2cTest https://doi.org/10.1124/jpet.105.084632Test |
| رقم الانضمام: | edsair.doi.dedup.....5ee44755abba114035dc208edea62e2c |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
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