STIM1 deficiency is linked to Alzheimer's disease and triggers cell death in SH-SY5Y cells by upregulation of L-type voltage-operated Ca2+ entry.
Pascual-Caro C, Berrocal M, Lopez-Guerrero AM, Alvarez-Barrientos A, Pozo-Guisado E, Gutierrez-Merino C, Mata AM, Martin-Romero FJ
J Mol Med (Berl). Oct 2018. doi: 10.1007/s00109-018-1677-y
Researchers from the Institute of Biomarkers of Molecular Pathologies (IBPM) of the University of Extremadura (UEx) have found that the protein STIM1 could be a new biomarker in sporadic Alzheimer's disease. Its role in neuronal deterioration has been proven thanks to the CRISPR-Cas9 technique using SH-SY5Y cell lines.
STIM1 is an endoplasmic reticulum protein with a role in Ca2+ mobilization and signaling. As a sensor of intraluminal Ca2+ levels, STIM1 modulates plasma membrane Ca2+ channels to regulate Ca2+ entry. In neuroblastoma SH-SY5Y cells and in familial Alzheimer's disease patient skin fibroblasts, STIM1 is cleaved at the transmembrane domain by the presenilin-1-associated γ-secretase, leading to dysregulation of Ca2+ homeostasis.
In this article, the authors investigated expression levels of STIM1 in brain tissues (medium frontal gyrus) of pathologically confirmed Alzheimer's disease patients, and observed that STIM1 protein expression level decreased with the progression of neurodegeneration. To study the role of STIM1 in neurodegeneration, a strategy was designed to knock-out the expression of STIM1 gene in the SH-SY5Y neuroblastoma cell line by CRISPR/Cas9-mediated genome editing, as an in vitro model to examine the phenotype of STIM1-deficient neuronal cells.
While STIM1 is not required for the differentiation of SH-SY5Y cells, it is absolutely essential for cell survival in differentiating cells. STIM1 deficiency triggers voltage-regulated Ca2+ entry-dependent cell death. Mitochondrial dysfunction and senescence are features of STIM1-deficient differentiated cells.
The authors conclude:
Altogether, the results prove that Cav1.2 upregulation is essential to trigger cell death in STIM1-deficient cells, a proposal that fits well with the protective effect of dihydropyridines against neurodegeneration in AD patients.