Methylamino-alanine as a Potential Trigger for Neurodegenerative Disorders

By: Thita Chanthasukh, Jihun Jung, Damin Lee

Abstract

Scientific researches predict that by 2040, neurodegenerative diseases will overtake cancer as the second most common cause of death among elders. Neurodegenerative disorders emerge when the neurons of the nervous system lose their functions and die. In turn, it may impair cognition, mobility, sensation, and the coordination of the body. Some of the most notorious neurodegenerative diseases are Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease. The effects and causes of these disorders are so diverse that even though they threaten millions of lives worldwide, many are yet to be discovered and cured.

In this paper, we will be examining one potential risk factor of neurodegenerative disorders, Beta-N-methylamino-L-alanine (BMAA). Although it has been years since discovery, a large part of the potential of BMAA still remains a mystery. BMAA is a nonprotein amino acid first discovered with the high incidence of Amyotrophic Lateral Schlartosis/Parkinsonism Dementia Complex (ALS/PDC) in Guam. It is essential to understand the mechanisms and dangers of BMAA because this neurotoxin can be prevalent in all levels of the trophic level due to biomagnification. As veterinarians, we should understand the consequences of BMAA as it can be incorporated into plant and animal proteins. We will discuss the discovery, effects, and neurological disorders of BMAA. Furthermore, we will conclude the paper by assessing the significance of BMAA in our studies.

The Discovery and Structure of BMAA

The Effect and Mechanism of BMAA

The Effect of BMAA on Glutamate-sensitive Receptors

The Effect of BMAA on Protein

Latency effect of BMAA

Potential Exposure to BMAA

Neurodegenerative Disorders

Since the detection of BMAA in Gaum, it has been postulated that BMAA may trigger several neurodegenerative diseases: Amyotrophic Lateral Sclerosis (ALS), Parkinsonism, Alzheimer’s disease, Lewy body disease, and progressive supranuclear palsy (PSP). Generally, neurodegenerative disorders are caused by protein misfolding and aggregation, with variations in the brain where it occurs.

Amyotrophic Lateral Sclerosis (ALS) is a motor neuron disease that progresses rapidly. Around 2.6 people per 100,000 per year in Europe while more than 1.5 per 100,000 per year in the United States with the average year of 47 to 63 are diagnosed with this disease (Odie Lastrawan et al, 2021). ALS can be identified into two types. Sporadic ALS occurs randomly without any clear risk factors. Familial ALS is inherited from a parent and makes up around 5 to 10% of all ALS cases due to the defect in the C9ORF72 gene. The role of BMAA on the etiology of ALS is still an area of uncertainty, but it has been proposed that the misincorporation of BMAA into SOD1, which is a Cu, Zu superoxide dismutase, promotes the onset of ALS. SOD1 is a protein coding gene. Specifically, BMAA replaces each serine in SOD1, structurally modifying SOD1 (Proctor and Dokholyan, 2019). Currently, ALS has no cure with only treatments to relieve symptoms. With the progressive loss of both lower and upper motor neurons, a patient suffers muscle weakness and paralysis and eventually dies.

A similar motor disease that BMAA is thought to induce is Parkinson’s disease (PD), though the disease is not considered fatal as ALS. 0.3% of the general population and 1% of the elders over 60 are estimated to have PD (García-Villa, 2022). PD is characterized by rigidity, tremor, bradykinesia, postural imbalance, or speech impediment (Nunes-Costa et al, 2020). The biomarker of PD is the presence of α-synuclein-containing (ASYN) insoluble fibrous aggregates, termed Lewy bodies (LBs), and the loss of neurons in substantia nigra. Misincorporation of BMAA into ASYN is a possible explanation for protein and misfolding that leads to the symptoms of PD. Alternative mechanisms suggest that BMAA strongly associates with melanin and by selectively inhibit the activity of certain enzymes (Nunes-Costa et al, 2020).

The etiology of notorious Alzheimer’s disease is still unknown today. Alzheimer's disease deteriorates memory and the ability to carry out any task. When the BMAA was discovered from patients suffering from ALS-PDC in Gaum around the 1970s. High amount BMAA was found in the mostportem brains of not only ALS-PDC patients but also in Canadians who died of AD (Holtcamp, 2012). Moreover in Florida, BMAA was detected in the dolphins with Aβ+ plaques, which is a hallmark of AD, supporting the hypothesis that BMAA is indeed associated with Alzheimer's disease (Davis et al ,2019). Although it was previously thought that BMAA can be one of the causations for Alzheimer's disease (AD), research from 2016 contests the accumulation of BMAA in the brain of patients diagnosed with AD. Brain samples of 20 AD patients and 20 AD control patients were analyzed for the presence of BMAA. However, it was found that none of this neurotoxin, either free or protein-bound, was detected in AD positive or negative patients (Meneely, 2016). In conclusion, this robust finding contributes to the controversy of BMAA’s role in AD up to date.

Conclusion

Lastly, we discussed the general information of Beta-N-methylamino-L-alanine (BMAA) and how it influences and aggregates neurodegenerative disorders. As acknowledged multiple times in the essay, extensive research is still required to cease the controversies existing regarding the presence of BMAA in certain diseases, like Alzheimer's disease. BMAA is also relevant to our studies since it serves as a great example of the trigger for glutamate receptors, which we learned about.

Reference