Protein folding is like doing origami where the amino acid sequence dictates how the protein folds to form its final 3D structure. This three-dimensional structure is essential to the proper functioning of the protein, and the same protein can be found in several conformations known as conformers. During protein synthesis, so-called chaperone molecules have the task of promoting normal folding. Several other factors can alter this structure under physiological conditions: for example, phosphorylation can modify a protein’s charges and make its enzymatic pocket accessible, thus activating the protein’s function (1, 2). On the other hand, when a protein folds into a structure that interferes with its function, or even its solubilization, leading to local toxicity and inflammation, we’re talking about a misfolded conformer (3). It’s like trying to fold a sheet of paper properly to make a swan, only to end up with a shapeless ball of paper.
Certain diseases, known as proteinopathies, are linked to the accumulation of misfolded conformers. One of the best known is Alzheimer’s disease, characterized by the accumulation of β-amyloid plaques. The development of amyotrophic lateral sclerosis (ALS) is associated with the accumulation of various misfolded conformers of SOD1, which lose their role in eliminating reactive oxygen species (ROS) from neurons (1). Several antisense mutations have been identified in the familial form of ALS (fSLA) (4). One promising therapeutic avenue is to prevent the synthesis of these misfolded conformers, using gene therapy approaches (5, 6). These include RNA interference methods, the approach used by Biogen to develop the first treatment for fSLA. Approved by the FDA last April (7), Qalsody (tofersen) is an injectable antisense RNA that reduces plasma levels of neurofilaments, a marker of neuronal damage, as well as the levels of SOD1 in the cerebrospinal fluid (8).
The use of antibodies that specifically recognize different versions of misfolded SOD1 conformers makes it possible to monitor disease progression in study models, distinguishing the swan from the paper ball. The MédiMabs team can help you select the right antibodies from our catalog (9), or develop de novo antibodies for your needs (10).