Calcipotriol inhibits α-synuclein aggregation in SH-SY5Y neuroblastoma cells by a Calbindin-D28k-dependent mechanism
| Autor: | Dean Louis Pountney, Alexandre N. Rcom-H'cheo-Gauthier, Adrian Cuda Banda Meedeniya |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Parkinson's disease Antineoplastic Agents medicine.disease_cause Biochemistry Calcium in biology 03 medical and health sciences Cellular and Molecular Neuroscience chemistry.chemical_compound Neuroblastoma Protein Aggregates 0302 clinical medicine Calcitriol Internal medicine Cell Line Tumor mental disorders medicine Humans Calcipotriol Alpha-synuclein Lewy body Dose-Response Relationship Drug business.industry Depolarization medicine.disease nervous system diseases Cell biology 030104 developmental biology Endocrinology nervous system chemistry Cell culture Calbindin 1 alpha-Synuclein business 030217 neurology & neurosurgery Oxidative stress |
| Zdroj: | Journal of neurochemistry. 141(2) |
| ISSN: | 1471-4159 |
| Popis: | Many neurodegenerative diseases are characterized by the formation of microscopically visible intracellular protein aggregates. α-Synuclein is the key aggregating protein in Parkinson's disease which is characterized by neuronal cytoplasmic Lewy body inclusions. Previous studies have shown relative sparing of neurons in Parkinson's disease and dementia with Lewy bodies that are positive for the vitamin D-dependent calcium-buffering protein, calbindin-D28k, and that α-synuclein aggregates are excluded from calbindin-D28k-positive neurons. Recent cell culture studies have shown that α-synuclein aggregation can be induced by raised intracellular-free Ca(II) and demonstrated that raised intracellular calcium and oxidative stress can act synergistically to promote α-synuclein aggregation. We hypothesized that calcipotriol, a potent vitamin D analogue used pharmaceutically, may be able to suppress calcium-dependent α-synuclein aggregation by inducing calbindin-D28k expression. Immunofluorescence and western blot analysis showed that calcipotriol potently induced calbindin-D28k in a dose-dependent manner in SH-SY5Y human neuroblastoma cells. Calcipotriol significantly decreased the frequency of α-synuclein aggregate positive cells subjected to treatments that cause raised intracellular-free Ca(II) (potassium depolarization, KCl/H2 O2 combined treatment, and rotenone) in a dose-dependent manner and increased viability. Suppression of calbindin-D28k expression in calcipotriol-treated cells using calbindin-D28k-specific siRNA showed significantly higher α-synuclein aggregation levels, indicating that calcipotriol-mediated blocking of calcium-dependent α-synuclein aggregation was dependent on the induction of calbindin-D28k expression. These data indicate that targeting raised intraneuronal-free Ca(II) in the brain by promoting the expression of calbindin-D28k at the transcriptional level using calcipotriol could prevent α-synuclein aggregate formation and ameliorate Parkinson's disease pathogenesis. |
| Databáze: | OpenAIRE |
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