Is There a Tangible Link Between Glyphosate Herbicide and ALS
Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a debilitating neurological disease that usually begins with weakness in the legs and ends in death within ﬁve years of the initial diagnosis due to lung paralysis. It is caused by destruction of the motor neurons in the spinal column which control muscle movements by relaying signals from the brain to the muscles. The incidence of ALS is increasing dramatically in the United States in the past two decades, in step with the dramatic increase in the use of glyphosate on core crops. Agricultural workers in the midwest, where the majority of the GMO Roundup Ready crops are grown, have more than ﬁve-fold increased risk to ALS compared to the general population.
These observations suggest that glyphosate, the active ingredient in the pervasive herbicide, Roundup, may play a causal role in the epidemic. In a recent paper , I collaborated with several colleagues to piece together the puzzle of a potential toxic mechanism of glyphosate to explain its role in ALS. In an earlier paper , Anthony Samsel and I had proposed that glyphosate’s main mechanism of toxicity to the body might be its ability to substitute for the coding amino acid glycine during protein synthesis by mistake. If this does happen, it would not be the ﬁrst time that a non-coding amino acid caused trouble by displacing a coding amino acid in proteins. In fact, there are at least nine naturally produced toxins that work exactly this way. One of these, Lcanavanine, was the cause of the death of Chris McCandless, the protagonist of the book, Into the Wild, by Jon Krakauer. Glyphosate herbicide’s main mode of action in weeds is believed to be suppression of a critical enzyme in the Shikimate pathway, which produces the aromatic amino acids. It is highly signiﬁcant that the bacterial gene that has been inserted into the DNA of GM crops to protect them from glyphosate has mutated so as to swap out a highly conserved glycine at the site of substrate binding in this enzyme. By replacing this glycine residue with alanine, three diﬀerent species of bacteria have produced a version of the enzyme that is completely insensitive to glyphosate. In the original Samsel and Seneﬀ paper , we discussed ALS as one of many diseases whose disease process can be directly explained by disruption of one or more crucial glycines in certain proteins. We spoke speciﬁcally about a protein called TDP-43, which has a glycine-rich region that is implicated in the disease process . Many cases of early-onset ALS are linked to genetic variants where one of the glycines in this region is mutated to a diﬀerent amino acid.
Glyphosate Substitution Causes Disruption Of Essential Protein
This leads to the obvious conclusion that these glycine residues are important for the proper function of TDP-43. The overwhelming majority of cases of ALS (90-95%) are not associated with any known genetic mutation. However, glyphosate substitution would cause the same kind of disruption of the protein that would happen through modiﬁcation of the genetic code, because a mistake is made in the process of translating the code into the peptide sequence. In the multi-author follow-on paper that focused on ALS , we were able to identify several other proteins with essential glycines that are implicated in the pathology of ALS. ALS is the end stage of a complex disease process that unfolds slowly over decades of elapsed time. As is true for many of the other diseases linked to glyphosate herbicide, ALS pathology begins in the gut with the disruption of gut microbes. Human cells don’t possess the shikimate pathway, but this biological pathway is used by our gut microbes to produce the essential aromatic amino acids for us. An important side eﬀect of the blocked pathway is that the substrate, phosphoenol pyruvate (PEP), accumulates. Ordinarily, the sugar, fructose, is converted to PEP and eventually to aromatic amino acids. However, because of the blockage, fructose also piles up unmetabolized. Glyphosate also interferes with at least two other pathways that normally start with fructose. The results of these disruptions are two fold: the gut becomes leaky and fructose remains unprocessed. Abdominal fat cells can take up the unmetabolized fructose and convert it into fat stores. However, a lean muscular body-type is deﬁcient in abdominal fat cells. In this case, the fructose is shipped from the gut to the liver, and the liver makes every eﬀort it can to grab up all the fructose and convert it to fat. Because glyphosate disrupts liver cytochrome P450 enzymes, the liver can not ship this fat out through the bile acids. Instead, it either produces excess serum LDL or stores the fat locally, inducing fatty liver disease. Fructose is ten times as strong as glucose as a glycating agent, causing the glycation damage to blood proteins that characterizes diabetes. Over time, the liver accumulates so much fat that it becomes diseased and can no longer keep up with clearing the fructose from the blood. Now, at least in the case of a lean, physically ﬁt, body type, the task of clearing the fructose falls on the skeletal muscles. The fast-twitch muscles that operate anaerobically by converting fructose to lactate are the most aﬀected. These muscles have to import many amino acids in order to maintain muscle protein, and they unintentionally take up glyphosate along amino acid transport channels. This glyphosate gets incorporated into the muscle proteins, disrupting their ability to function properly. One protein in particular is noteworthy: myosin. Myosin is a “molecular motor” and it is crucial for muscle contraction and therefore for movement. Remarkably, myosin contains a glycine residue at position 699 that is absolutely essential for its function . If this glycine is replaced by alanine (one extra methyl group), the molecule drops to only 1% of its capacity as a motor. If only 2% of the myosin molecules in a muscle are swapped with alanine in place of glycine, the muscle drops to 50% capacity, because the broken motors get in the way of the healthy ones.
Glyphosate Disrupts Body Efficiency In Myriad Ways
Once the muscle starts to become disabled, the motor neurons supplying these muscles have to go into overdrive to get them to move. This means increased activity, increased exposure to neurotoxic molecules such as glutamate, increased uptake of glyphosate, and failed molecular motors in the motor neurons. Other motors besides myosin are essential in the motor neurons for pulling mitochondria up and down the long axon reaching to the synapse with the muscle cell. These motors also depend strongly on glycine, so they too can succumb to glyphosate poisoning by substitution for glycine. TDP-43’s normal role in the cell is not entirely understood. It appears that it is able to sequester proteins into a state of hibernation, and it does this under conditions of stress. Certainly glyphosate induces stressful conditions. Once glyphosate gets into the protein, it appears that it irreversibly forms conglomerates of misfolded proteins that disrupt the motor neuron’s activities, much like the amyloid beta plaque associated with Alzheimer’s disease. Other proteins, including an important one in the mitochondria that supplies energy to the cell, and another one that protects the cell from oxidative damage, also contain essential glycines that are vulnerable to glyphosate substitution. The progression from gut dysbiosis to liver disease to muscle failure to motor neuron damage probably happens over a period of decades, as glyphosate slowly accumulates in the tissues. Risk factors for ALS include a high fructose diet and an athletic lean physique with a lifestyle that maintains a high level of physical ﬁtness. Mineral deﬁciencies and mineral imbalances are also implicated, especially copper and zinc deﬁciency alongside excess dietary manganese. Glyphosate compounds the problem of mineral imbalances because of its ability to chelate minerals, making them unavailable and disrupting the normal mechanisms by which they are distributed throughout the body. Obviously, if our analysis is correct, it is very important to eat a 100% certiﬁed organic diet to guard against a future diagnosis of ALS.
by Stephanie Seneﬀ
 Seneﬀ S, Morley W, Hadden MJ, Michener MC. Does glyphosate acting as a glycine analogue contribute to ALS? J Bioinfo Proteomics Rev 2016: 2(3): 1-21.
 Samsel A and Seneﬀ S. Glyphosate, pathways to modern diseases V: Aminos acid analogue of glycine in diverse proteins. Journal of Biological Physics and Chemistry 2016;16:9-46.
 Pesiridis S, Lee V M-Y, Trojanowski JQ. Mutations in TDP-43 link glycine-rich domain functions to amyotrophic lateral sclerosis. Hum Mol Genet 2009; 18(R2): R156-R162.
 Kinose F, Wang SX, Kidambi US, Moncman CL, Winkelmann DA. Glycine 699 is pivotal for the motor activity of skeletal muscle myosin. J Cell Biol. 1996;134(4):895-909.