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

Brain and Behavior
Philip Wing-Lok HoShu-Leong Ho

Abstract

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. 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. 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. Ou...Continue Reading

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Citations

Dec 29, 2015·Biochimica Et Biophysica Acta·Rita PadányiÁgnes Enyedi
Aug 3, 2016·Biochemical and Biophysical Research Communications·Marisa BriniTito Calì
Jun 2, 2017·Physiological Reviews·Nicholas StaffordElizabeth J Cartwright
Sep 11, 2019·Cold Spring Harbor Perspectives in Biology·Jialin ChenPeter Vangheluwe
Jun 8, 2017·Frontiers in Physiology·Sarah Y T RobertsonMichael L Paine
Jun 8, 2021·Frontiers in Immunology·Maylin Merino-WongDalia Alansary

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Methods Mentioned

BETA
PCR
confocal microscopy

Software Mentioned

GraphPad
Prism

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