Amyotrophic lateral sclerosis, an incurable, progressive nervous system disease that affects nerve cells in the brain and spinal cord, causing loss of muscle control, is incurable. Often called Lou Gehrig’s disease after the American baseball player who was diagnosed with it, the cruel disorder affects as many as 30,000 in the US alone, with 5,000 new cases diagnosed each year. Estimates suggest that ALS is responsible for as many as five of every 100,000 deaths in people aged 20 or older. 

Early symptoms of ALS include stiff muscles, muscle twitches and gradual increasing weakness and muscle wasting. Half of the victims develop at least mild difficulties with thinking and behavior, and about 15% develop frontotemporal dementia. Most people experience pain. The affected muscles are responsible for chewing food, speaking, and walking. Motor neuron loss continues until the ability to eat, speak, move, and finally the ability to breathe is lost. ALS eventually causes paralysis and early death, usually from respiratory failure. 

Researchers are struggling to find ways of helping ALS victims, but it will be accomplished only step by step. Now, Tel Aviv University (TAU) researchers have deciphered critical features of a protein behind ALS/ 

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 (ER) 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. Yet, even though S1R has been studied intensively, basic aspects remained controversial, such as S1R topology and whether it reaches the cell membrane.

The new study led by TAU researcher Prof. Gerardo Lederkremer from the Shmunis School of Biomedicine and Cancer Research and Sagol School of Neuroscience, together with Prof. 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 prestigious Journal of Biological Chemistry under the title: “The Sigma-1 receptor is an ER-localized type II membrane protein.” 

Lederkremer explained that “proteins, much like a bipolar magnet, have two ends – carboxy (-COOH group) and amino (-NH2 group). 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, 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 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 – we hope – alleviate the suffering of neurodegenerative patients, especially those with ALS. In this field. every small step is a significant advance.”