Calcipotriol inhibits α‐synuclein aggregation in SH‐SY5Y neuroblastoma cells by a Calbindin‐D28k‐dependent mechanism. Issue 2 (April 2017)

• Record Type: Journal Article
• Authors: Rcom‐H'cheo‐Gauthier, Alexandre N.; Meedeniya, Adrian C. B.; Pountney, Dean L.
• Is Part Of: Journal of neurochemistry. Volume 141:Issue 2(2017)
• Page Start: 263
• Page End: 274
• Publication Date: 2017-04
• Subjects: alpha‐synuclein -- calbindin‐D28k -- calcipotriol -- calcium -- oxidative stress -- Parkinson's disease; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.13971
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: 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. Abstract : Alpha‐synucleinopathy neurodegenerative diseases, such as Parkinson's disease, are associated with abnormal, aggregation of the protein, α‐synuclein, that evidence suggests can be triggered by raised intraneuronal‐free calcium. Calcipotriol, a vitamin D analogue, suppressed calcium‐dependent α‐synuclein aggregation and conferred neuroprotection by inducing expression of the calbindin‐D28k calcium‐buffering protein in SH‐SY5Y human neuroblastoma cells. Targeting raised intraneuronal‐free calcium in the brain by promoting the expression of calbindin‐D28k by using calcipotriol could prevent α‐synuclein aggregate formation and ameliorate Parkinson's disease pathogenesis.