Importance of calcium in Parkinson’s disease pathophysiology
IR@IICB: CSIR-Indian Institute of Chemical Biology, Kolkata
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| Title |
Importance of calcium in Parkinson’s disease
pathophysiology
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| Creator |
Singh, Alpana
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| Subject |
Cell Biology & Physiology
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| Description |
Parkinson Disease (PD) is the most common progressive neurodegenerative movement disorder
characterized by preferential loss of ventral midbrain dopaminergic neurons of substantia nigra
pars compacta. It has been recently suggested that high Ca2+ levels due to Cav1.3 channeldependent
pacemaking activity may contribute to SNpc susceptibility in PD. Based on this, in the
present study, we hypothesized that perturbed neuronal calcium homeostasis is one of the major
factors in the genesis of PD, and examined the mechanism of dopaminergic neuronal protection
provided by nimodipine, an L-type calcium channel blocker in cellular and animal models of the
disease. We used the pakinsonian neurotoxin, MPP+ in SH-SY5Y, MPTP in mice to induce PD
pathology and/or behavioral phenotypes and employed parkinsonian cybrids to study the PD
phenotype. Cell viability via MTT assay, calcium imaging employing Fura-2AM, mitochondrila
morphology by Mitotracker Green and mitochondrial membrane potential using TMRM were
investigated in SH-SY5Y cells. Animal behaviors were monitored, striatal dopamine levels were
measured employing HPLC-electrochemical detection procedure and nigral neuronal loss was
determined using tyrosine hydroxylase immunohistochemistry. Mitochondrial integrity and their
functions were examined using DCFDA fluorescence and oxygen consumption analysis. In SHSY5Y
cells, pretreatment with nimodipine attenuated MPP+-mediated increase in intracellular
calcium, reduction in cell viability, decrease mitochondrial membrane potential and corrected the
aberrations in mitochondrial morphology. In mice, MPTP-induced behavioral dysfunctions
(reduced swimming ability, akinesia and catalepsy), striatal dopamine depletion, increases in
mitochondrial reactive oxygen species generation and loss in mitochondrial respiration were
corrected by nimodipine administration. The level of intracellular calcium was elevated in PD
cybrids. Further, the expression of calcium binding protein calbindin as measured by real time
PCR and Immunoblot, was found to be decreased while that of calcium activated phosphatase
calcineurin B and protease calpain protein levels were found to be increased after the neurotoxin
treatment, while this trend was significantly attenuated following nimodipine treatment (both in
vitro and in vivo). These results suggest that the L-type calcium channel blocker, nimodipine
protects against the parkinsonian neurotoxin-induced cell death by correcting the defects in
mitochondrial integrity and functions, caused by increased intracellular calcium in dopaminergic
neurons.
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| Date |
2016
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| Type |
Thesis
NonPeerReviewed |
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| Format |
application/pdf
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| Identifier |
http://www.eprints.iicb.res.in/2583/1/Alpana_Singh_Thesis_.pdf
Singh, Alpana (2016) Importance of calcium in Parkinson’s disease pathophysiology. PhD thesis, C U. |
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| Relation |
http://www.eprints.iicb.res.in/2583/
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