A candidate gene of Alzheimer diseases was mutated in senescence-accelerated mouse prone (SAMP) 8 mice

https://doi.org/10.1016/j.bbrc.2021.07.095Get rights and content
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Highlights

  • We identified a polymorphism of Slc24a4 that has been postulated as one of the candidate genes of late onset Alzheimer's diseases (LOAD), through quantitative trait linkage analysis of senescence-accelerated mouse prone (SAMP) 8 strain exhibiting age related learning and memory deficiency.

  • •Spliced isoform of mouse Slc24a4 showed both expression and function of Na+/(Ca2+-K+) exchanger predominantly compared to full isoform.

  • •SAMP8 type polymorphic Slc24a4-T413 M showed dysfunctional Na+/(Ca2+-K+) exchanger activity in HEK293 cells compared with that of wild type (Slc24a4-WT).

Abstract

The senescence-accelerated mouse prone (SAMP) 8 strain exhibits age-related learning and memory deficits (LMD) at 2 months of age. We have found strong association of chromosome 12 locus with learning memory deficit (LMD) phenotype in SAMP8 strain. In the course of searching candidate gene, here we identified solute carrier family 24 sodium/potassium/calcium exchanger member 4 (Slc24a4) in SAMP8 chromosome 12 LMD possessing one single nucleotide polymorphism causing amino acid replacement of Threonine at 413 position with Methionine. Since SLC24A4 has been postulated as a candidate of late onset Alzheimer's diseases (LOAD), we further analyze the functional importance of this polymorphism. By expressing Slc24a4 protein in HEK293 cells, here we showed polymorphic SAMP8 type Slc24a4-T413 M causing significant loss of calcium ion (Ca2+) transporter activity in cells compared with that of wild type mouse (Slc24a4-WT). However, no study yet shows any functional association of human SLC24A4 polymorphism with the onset of LOAD pathogenesis. Thus, our present finding may further help to clarify the importance of this ion exchanger with age related cognitive dysfunction.

Keywords

SAMP8
Chromosome 12
Slc24a4 polymorphism
Loss of transporter activity
Ca2+ ion dysregulation
Alzheimer diseases

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