Journal News

Researchers decipher critical features of a protein behind ALS

Tomer Velmer
By Tomer Velmer
Dec. 25, 2021

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.

A new study 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. Read the original.

Enjoy reading ASBMB Today?

Become a member to receive the print edition four times a year and the digital edition monthly.

Learn more
Tomer Velmer
Tomer Velmer

Tomer Velmer is the spokesperson and head of media relations at Tel Aviv University.

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

How signals shape DNA via gene regulation
Journal News

How signals shape DNA via gene regulation

Aug. 19, 2025

A new chromatin isolation technique reveals how signaling pathways reshape DNA-bound proteins, offering insight into potential targets for precision therapies. Read more about this recent MCP paper.

A game changer in cancer kinase target profiling
Journal News

A game changer in cancer kinase target profiling

Aug. 19, 2025

A new phosphonate-tagging method improves kinase inhibitor profiling, revealing off-target effects and paving the way for safer, more precise cancer therapies tailored to individual patients. Read more about this recent MCP paper.

How scientists identified a new neuromuscular disease
Feature

How scientists identified a new neuromuscular disease

Aug. 14, 2025

NIH researchers discover Morimoto–Ryu–Malicdan syndrome, after finding shared symptoms and RFC4 gene variants in nine patients, offering hope for faster diagnosis and future treatments.

Unraveling cancer’s spaghetti proteins
Profile

Unraveling cancer’s spaghetti proteins

Aug. 13, 2025

MOSAIC scholar Katie Dunleavy investigates how Aurora kinase A shields oncogene c-MYC from degradation, using cutting-edge techniques to uncover new strategies targeting “undruggable” molecules.

How HCMV hijacks host cells — and beyond
Profile

How HCMV hijacks host cells — and beyond

Aug. 12, 2025

Ileana Cristea, an ASBMB Breakthroughs webinar speaker, presented her research on how viruses reprogram cell structure and metabolism to enhance infection and how these mechanisms might link viral infections to cancer and other diseases.

Understanding the lipid link to gene expression in the nucleus
Profile

Understanding the lipid link to gene expression in the nucleus

Aug. 11, 2025

Ray Blind, an ASBMB Breakthroughs speaker, presented his research on how lipids and sugars in the cell nucleus are involved in signaling and gene expression and how these pathways could be targeted to identify therapeutics for diseases like cancer.