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Brain Behav. 2015 Apr;5(4):e00321. doi: 10.1002/brb3.321. Epub 2015 Feb 16.

PMCA4 (ATP2B4) mutation in familial spastic paraplegia causes delay in intracellular calcium extrusion.

Author information

1
Division of Neurology, Department of Medicine, University of Hong Kong Hong Kong, China ; Research Centre of Heart, Brain, Hormone and Healthy Aging, University of Hong Kong Hong Kong, China.
2
Division of Neurology, Department of Medicine, University of Hong Kong Hong Kong, China.
3
Department of Psychiatry, University of Hong Kong Hong Kong, China ; Centre for Reproduction, Development and Growth, University of Hong Kong Hong Kong, China ; Centre for Genomic Sciences, University of Hong Kong Hong Kong, China.

Abstract

BACKGROUND:

Familial spastic paraplegia (FSP) is a heterogeneous group of disorders characterized primarily by progressive lower limb spasticity and weakness. More than 50 disease loci have been described with different modes of inheritance. Recently, we described a novel missense mutation (c.803G>A, p.R268Q) in the plasma membrane calcium ATPase (PMCA4, or ATP2B4) gene in a Chinese family with autosomal dominant FSP. Further to this finding, here we describe the functional effect of this mutation.

METHODS:

As PMCA4 removes cytosolic calcium, we measured transient changes and the time-dependent decay of cytosolic calcium level as visualized by using fura-2 fluorescent dye with confocal microscopy in human SH-SY5Y neuroblastoma cells overexpressing either wild-type or R268Q mutant PMCA4.

RESULTS:

Overexpressing both wild-type and R268Q PMCA4 significantly reduced maximum calcium surge after KCl-induced depolarization as compared with vector control cells. However, cells overexpressing mutant PMCA4 protein demonstrated significantly higher level of calcium surge when compared with wild-type. Furthermore, the steady-state cytosolic calcium concentration in these mutant cells remained markedly higher than the wild-type after SERCA inhibition by thapsigargin.

CONCLUSION:

Our result showed that p.R268Q mutation in PMCA4 resulted in functional changes in calcium homeostasis in human neuronal cells. This suggests that calcium dysregulation may be associated with the pathogenesis of FSP.

KEYWORDS:

ATP2B4; Familial spastic paraplegia; PMCA; calcium transient; neurodegeneration

PMID:
25798335
PMCID:
PMC4356846
DOI:
10.1002/brb3.321
[Indexed for MEDLINE]
Free PMC Article

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