Anavex Life Sciences Corp (AVXL)

[Investor2014]

New biomarker for Alzheimer's disease found thanks to the CRISPR technique

One of the alterations observed due to the deficiency of STIM1 is in the transport of calcium ions through the plasma membrane of the neurons. "This calcium is necessary for the cell to be fully viable, and an alteration in this process affects its entire physiology, finally causing its death. The cell is unable to halt the transport of calcium, which becomes unregulated and out of control", states Martin-Romero. The investigator highlights that this transport takes place through calcium ion channels regulated by a voltage. These voltage-gated calcium channels, the so-called L-type, can be blocked using pharmaceuticals based on dihydropyridine. In fact, the team of researchers was able to halt cell death in vitro using pharmaceuticals based on dihydropyridine because of that blocking action, representing an important new finding in the treatment of Alzheimer's.

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

Abstract
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 ?-secretase, leading to dysregulation of Ca2+ homeostasis. In this report, we 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. It was proved that, while STIM1 is not required for the differentiation of SH-SY5Y cells, it is absolutely essential for cell survival in differentiating cells. Differentiated STIM1-KO cells showed a significant decrease of mitochondrial respiratory chain complex I activity, mitochondrial inner membrane depolarization, reduced mitochondrial free Ca2+ concentration, and higher levels of senescence as compared with wild-type cells. In parallel, STIM1-KO cells showed a potentiated Ca2+ entry in response to depolarization, which was sensitive to nifedipine, pointing to L-type voltage-operated Ca2+ channels as mediators of the upregulated Ca2+ entry. The stable knocking-down of CACNA1C transcripts restored mitochondrial function, increased mitochondrial Ca2+ levels, and dropped senescence to basal levels, demonstrating the essential role of the upregulation of voltage-operated Ca2+ entry through Cav1.2 channels in STIM1-deficient SH-SY5Y cell death.

Seems relevant to A2-73 and Calcium Homeostasis.