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Calcipotriol inhibits α‐synuclein aggregation in SH ‐ SY 5Y neuroblastoma cells by a Calbindin‐D28k‐dependent mechanism
Author(s) -
RcomH'cheoGauthier Alexandre N.,
Meedeniya Adrian C. B.,
Pountney Dean L.
Publication year - 2017
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13971
Subject(s) - calcipotriol , mechanism (biology) , chemistry , calbindin , microbiology and biotechnology , cancer research , biology , calcium , immunology , philosophy , epistemology , psoriasis , organic chemistry
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 ‐ SY 5Y 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, KC l/H 2 O 2 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 si RNA 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.