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The Sigma-1 receptor (S1R) is a transmembrane protein with important roles in stabilizing cellular functions in both normal physiology and disease. Especially in neurodegenerative diseases, S1R's activity has been shown to provide neuronal protection by stabilizing the cell environment (based on the movement of calcium ions), improving mitochondrial function and reducing a damaging cellular stress caused by the diseases, called endoplasmic reticulum stress. Drugs are now being developed to try to boost these cell protective S1R activities in several diseases.

S1R missense mutations are one of the causes of distal hereditary motor neuronopathies and amyotrophic lateral sclerosis (also known as Lou Gehrig’s disease). ALS is the ailment that afflicted renown late physicist Stephen Hawking. Yet, even though S1R has been studied intensively, basic aspects remained controversial, such as S1R topology and whether it reaches the cell membrane.

led by Tel-Aviv University researcher Gerardo Lederkremer from the Shmunis School of Biomedicine and Cancer Research and Sagol School of Neuroscience, together with Nir Ben Tal from the School of Neurobiology, Biochemistry and Biophysics, and students in their labs, sheds light on some of these important questions. The study was recently published in the Journal of Biological Chemistry.

“Proteins, much like a bipolar magnet, have two ends — carboxy (-COOH group) and amino (-NH2 group)," said Lederkremer. "In one trial, we tagged the carboxy end (C-terminal tagging) and found that the protein is set in a specific orientation on internal membranes of the cell, where the amino end faces the cytoplasm. In another approach, we tagged the amino end and found equal probability for both possible orientations.”

These findings provide an explanation for current contradictions in the literature regarding the favored orientation, as the tagging itself affects the receptor’s topology — “an act of observation which affects the observed system.” Therefore, said Lederkremer, “we applied other approaches, called protease protection assay and glycosylation mapping, which showed incontrovertibly that S1R assembles so that the amino end faces the cytoplasm. Moreover, using additional approaches we found that the receptor is retained in the ER and hardly exits to the cell surface. This finding explains how the S1R functions in the ER and reduces the pathogenic ER stress”.

Lederkremer said he is optimistic about the new findings: “Having deciphered a crucial mechanism in the receptor's function, we have no doubt that our new findings can affect therapeutic approaches based on S1R, and hopefully alleviate the suffering of neurodegenerative patients, especially those with ALS. In this field every small step is a significant advance.”

This article was reprinted with permission from Tel Aviv University.