Open AccessPMCA 4 ( ATP 2B4) mutation in familial spastic paraplegia causes delay in intracellular calcium extrusion
Author(s) -
Ho Philip WingLok,
Pang Shirley YinYu,
Li Miaoxin,
Tse Zero HoMan,
Kung Michelle HiuWai,
Sham PakChung,
Ho ShuLeong
Publication year - 2015
Publication title -
brain and behavior
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.915
H-Index - 41
ISSN - 2162-3279
DOI - 10.1002/brb3.321
Subject(s) - calcium , biology , plasma membrane ca2+ atpase , wild type , thapsigargin , mutant , calcium in biology , microbiology and biotechnology , calcium pump , mutant protein , calcium metabolism , mutation , medicine , endocrinology , chemistry , intracellular , biochemistry , gene , atpase , enzyme
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 ATP ase ( PMCA 4, or ATP 2B4) gene in a Chinese family with autosomal dominant FSP . Further to this finding, here we describe the functional effect of this mutation. Methods As PMCA 4 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 ‐ SY 5Y neuroblastoma cells overexpressing either wild‐type or R268Q mutant PMCA 4. Results Overexpressing both wild‐type and R268Q PMCA 4 significantly reduced maximum calcium surge after KC l‐induced depolarization as compared with vector control cells. However, cells overexpressing mutant PMCA 4 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 PMCA 4 resulted in functional changes in calcium homeostasis in human neuronal cells. This suggests that calcium dysregulation may be associated with the pathogenesis of FSP .