Mutations causing S1R dysfunction are one of the causes of ALS (muscular dystrophy) and hereditary motor neuropathy. In another context, this receptor is a target site for the drug cocaine
Sigma-1 type receptor (S1R) is a transmembrane protein that plays important roles in stabilizing cell functions, both in a normal physiological state and during disease. In particular, in neurodegenerative diseases (degenerative diseases of various kinds), the activity of S1R has been shown to be able to provide neurological protection to nerve cells by changing the communication between the cell and its environment (based on the movement of calcium ions), improving mitochondrial function and reducing the pressure within the endoplasmic reticulum (a cell organelle).
Mutations causing S1R dysfunction are one of the causes of ALS (muscular dystrophy) and hereditary motor neuropathy. In another context, this receptor is a target site for the drug cocaine.
Although S1R has been intensively studied, several fundamental aspects remain controversial, including the topology of the receptor and its ability or inability to reach the cell membrane.
A new study led by a researcher from Tel Aviv University, Prof. Harardo Ledkermer from the Shemunis School of Biomedical Research and Cancer Research, in collaboration with Prof. Nir Ben Tal from the School of Neurobiology, Biochemistry and Biophysics, along with some of their students, tries to shed light on some of these questions. The research was recently published in the prestigious Journal of Biological Chemistry.
Prof. Horedado Lederkramer: "Proteins have two ends, a carboxyl end (COOH- group) and an amino end
(NH group3-), similar to a magnet with two poles. In one approach, we marked the carboxyl end (C-terminal tagging), and it is clear that the protein is placed in a certain orientation on the internal membranes of the cell, where the amino end faces the cytoplasm. In a different approach, we marked the N-terminal tagging and accepted that both options are equally likely."
These findings are the most likely explanation for the contradictions that exist in the literature regarding the preferred orientation, since the very marking itself affects the topology of the receptor - that is, a measurement that affects the observation. Therefore, says Prof. Laderkramer, "we tried to use other methods, called 'protease protection test' and 'glycosylation mapping', and these showed unequivocally that S1R usually organizes itself so that the amino end faces the cytoplasm. Apart from this, we found, with additional analysis methods, that the receptor is anchored in the endoplasmic reticulum and almost does not come out to the cell membrane at all. This finding explains the reduction of pressure inside the retina that causes diseases."
Prof. Lederkramer is optimistic about the implications of the new findings: "Since we were able to decipher a critical mechanism in the function of the receptor, we have no doubt that the findings may have an impact on the therapeutic approaches based on S1R, and hopefully provide relief for the tremendous suffering of patients with various neurodegenerative diseases, primarily ALS. Every small step is a significant step in this field."
More of the topic in Hayadan:
- Searching for the genetic roots of ALS in new territories
- For the first time: genetic mapping of all ALS patients in Israel
- Immunity Pharma announces the start of a clinical study in ALS patients with the original drug IPL344
- First case of euthanasia in Israel: the Attorney General allowed the judge to allow euthanasia for an ALS patient who requested it
- Researchers have discovered a new component of selective damage in the muscular dystrophy disease ALS
