Insights into possible treatments for disorders that range from demyelination to plaque formation and misfolded proteins.
The effects of neurodegenerative diseases range from demyelination to plaque formation and misfolded proteins.
Current treatment and prevention methods are limited, mainly due to not fully understanding the mechanism of pathology. Amyotrophic lateral sclerosis (ALS), or Lou Gehrig’s disease, is a nerve degenerative disease that causes progressive muscle weakness. Sporadic ALS, which has been observed notably in the United Staates, Guam, France, and in areas around the Baltic Sea, has been attributed to increased levels of β-methylamino-L-alanine (BMAA). The gene-time-environment hypothesis suggests a multiple cause of a disease rather than a single factor. BMAA is thought to be a potential environmental risk factor to sporadic ALS due to diet.1
BMAA has been found in the brains of ALS and other neurodegenerative patients. Having a similar structure to amino acids, BMAA alone can act as L-serine, which then can be incorporated into human proteins causing misfolding. However, a distinctly destructive property noted in BMAA is when it undergoes N-nitrosation (adding a nitro to the amine group). This process makes N-BMAA, a cytotoxic DNA damaging alkylating agent. BMAA is synthesized by cyanobacteria, ingested by humans. and has been found in the food and animals studied in Guam. In a study that used the SH-SY5Y immortalized neuroblastoma cell line (has many characteristics of neuronal cells and commonly used in ALS and Alzheimer’s studies), BMAA was minimally toxic; however, N-BMAA toxicity was similar to the positive control (5M NaCl) at 96 hours. It should be noted that there was a statistical difference at all time points, showing immediate N-BMAA neurotoxicity.1, 2
Possible Effects of BMAA outside of ALS
When reacting with bicarbonate ions, BMAA forms β-carbonate, which is a structural analogue of glutamate. In this structure, the molecule can now bind to glutamate receptors, including Alzheimer’s treatment target N-methyl-D-aspartate (NMDA), leading to excitotoxicity, a process that leads to increased intracellular sodium and calcium levels, reactive oxygen species (ROS), and ultimately, cell death.2
BMAA in-vitro and Treatment with L-serine
In an in-vitro study, tests were run to identify cell viability and ER stress of BMAA with incorporating L-serine as a treatment. No significant change in viability was seen in control versus BMAA versus BMAA+L-serine. However, there were morphological changes to the BAMA-exposed SH-SY5Y cells. ER stress in this cell observation is due to accumulation of misfolded or unfolded proteins in the ER (endoplasmic reticulum) lumen. CHOP is a transcription factor (C/EBP homologous protein) that activates under ER stress and incorporates a deletion mechanism to protect the body. In this study, no change was seen in the initial 24 hours; however, a statistical difference (increase in CHOP) with BMAA exposed cells was seen at 48 hours (p≤0.001). In L-serine-treated BMAA-exposed cells at 48 hours, the increase was prevented (CHOP expression did not increase), keeping L-serine treated cell activity similar to the control (p≤0.0001).
Caspase-3 is an irreversible apoptosis initiator. Prolonged ER stress has been linked to the upregulation of this enzyme and ultimately leading to cell death. At 72-hour incubation, Caspase-3 activity was significantly increased when treated with BMAA (p≤0.05). This increase was prevented when L-serine was added to BMAA treated cells (p≤0.05).1
Astrocytes in the human body produce L-serine, and the average American diet consists of about 3.5 grams of L-serine a day. The FDA states L-serine is generally regarded as safe, as long as it consists of no more than 8.4% of total protein in the diet (CFR Title 21 Section 17.320.18). A 6-month phase I randomized double blind (pharmacist unblinded) trial was conducted to assess safety of doses 0.5, 2.5, 7.5, and 15g twice a day.
To be eligible, patients must have an FVC >60%. Three people died, in each case due to disease progression and starting the trial with the lowest baseline FVC (unrelated to the dose given). Considering there was no control group, the patients were compared to placebo patients in 5 other ALS clinical trials. The primary outcome had shown safety at all doses. The secondary results were developed by comparing the altered decline of functionality, measured by ALSFRS-R (ALS Functional Rating Scale — Revised) scores and FVC, with the matched placebo group. The slope of ALSFRS-R score with 15g dosing had shown an 85% reduction (p=0.014), while FVC and symptom duration had shown a decline in slope in regards to events per month (p=0.044). It is important to note that as dose increased per gram, the reduction in slope for ALSFRS-R decreased. This trial has many limitations, such as sample size and using other trials to match patients in this trial to develop the comparative slope; however, it gives enough promise to warrant further investigation. A phase II, 9 month trial is planned.
What Does This Mean?
Could L-serine supplementation aid in preventing misfolding for neurological diseases other than ALS, such as Parkinsonism or dementia? Results from brain tissue samples of ALS and AD patients has shown BMAA in the tissue.4 Those who are at an environmental (or possibly genetic) risk of neurodegenerative disease, may benefit from supplementation of L-serine with 15 g twice daily dosing. If beneficial, new genetic susceptibility testing through sources such as 23&me may be a tool in allowing preventative measures to be taken through diet in those susceptible of developing neurodegenerative diseases.
L-serine may or may not be a treatment or prevention for some neurological conditions, but it invites the question: Could specific amino acid supplementation be used to prevent neurological conditions such as ALS, Alzheimer’s, or other conditions for those at risk? Finally, it should be noted that BMAA is specifically found to affect proteins in humans, not in bacteria or BMAA-treated monkeys. Knowing this, genomic analysis could be used as a possibility for treatment findings through bioinformatics processing.
1. Main BJ, Dunlop RA, Rodgers KJ. The use of L-serine to prevent β-methylamino-L-alanine (BMAA)-induced proteotoxic stress in vitro. Toxicon. 2016;109:7-12. doi: 10.1016/j.toxicon.2015.11.003.
2. Potjewyd G, Day PJ, Shangula S, et al. L-β-N-methylamino-l-alanine (BMAA) nitrosation generates a cytotoxic DNA damaging alkylating agent: An unexplored mechanism for neurodegenerative disease. Neurotoxicology. 2017;59:105-109. doi: 10.1016/j.neuro.2017.01.007.
3. Levine TD, Miller RG, Bradley WG, et al. Phase I clinical trial of safety of L-serine for ALS patients. Amyotroph Lateral Scler Frontotemporal Degener. 2017;18(1-2):107-111. doi: 10.1080.21678421.2016.1221971.
4. Pablo J, Banack SA, Cox PA, et al. Cyanobacterial neurotoxin BMAA in ALS and Alzheimer's disease. Acta Neurol Scand. 2009;120(4):216-25. doi: 10.1111.j.1600-0404.2008.01150.x.