Western Pacific ALS/P-D: Exploration of potential Cycad plant toxicity
Clusters of disease showing amyotrophic lateral sclerosis, parkinsonism-dementia, or an overlap of symptoms of both diseases (Western Pacific ALS/P-D) affected local individuals during a recent limited historical period on the island of Guam, the Kii pensisula of Japan, and a portion of New Guinea (3). In Guam, the local disease is commonly called lytico-bodig. The preponderance of data collected to date strongly suggests an environmental cause for Western Pacific ALS/P-D. Cycad plant exposure has been identified as common to the three geographic sites (3). In Guam, individuals reported an increase in consumption of Cycad flour during the lifetimes of those affected with the disease. Cycad seeds have been used by local individuals in the affected area of New Guinea for topical wound care as a poultice, including for deep wounds. Cycad has also been available in some affected regions as an oral medication. Cycad exposure has been considered by many to be the most likely cause of Western Pacific ALS/P-D. A number of other theories have also been explored. While intense interest remains in understanding Western ALS/P-D, the cause has not been confirmed to date.
Because raw cycad consumption by humans and animals is well-documented to cause a potent neurotoxic effect, called neurocycadism, with acute poisoning signs and often long-term non-progressive neurologic deficits, it is accepted that cycads contain neurotoxin(s) (3). To that end, neurotoxic chemicals produced by the cycad plant such as cycasin (methylazoxymethanol (MAM)) have been studied as possible causes of the progressive, slower disease of Western Pacific ALS/P-D. However, a clear link of cycads to ALS/P-D has not yet been established.
It may be useful to consider additional hypotheses as to how cycad exposure could cause a progressive neurologic disease resembling ALS/P-D. Here we will for interest and exploration reconsider the cycad hypothesis in the light of the Lipid-carrier initiator hypothesis. One may consider the following potential factors in cycads that could promote prion formation.
Cycad seeds contain lipids, such as plant seed lipid-bodies, that are often in the form of vesicles or spherules. (4). These may be long-lasting and are stabilized by proteins, including caleosin in cycads. These could be a potential source of initiators . One should also note that clay was sometimes used in the process of cycad flour preparation, and the mineral-lipid hypothesis should not be entirely excluded. For example, there is a description that those preparing cycad seeds would often coat their hands in clay during the process. Clay minerals can bind and hold neurotoxins, and can combine with lipids to make vesicles. A number of plants produce antimicrobial peptides (AMPs), to aid in defense of the plant against infection. Cycad plants produce three known antimicrobial peptides, named Cy-AMP1, Cy-AMP2, and Cy-AMP3 (5). Cy-AMP3 may be related to lipid transfer. The majority of Cy-AMPs have significant cysteine, proline and glycine content (5). I note with relationship to the lipid-carrier initiator hypothesis that these amino acids are associated with beta-sheet tendencies, making the Cy-AMPs possible secondary initiators, and that AMPs are amphiphilic, so one might consider that they could interact with target protein and associate with primary initiator lipid particles. AMPs have several membrane and lipid-related effects, including the capacity to disrupt and alter membranes, to form smaller particles from the lipid bilayer, to form non-lamellar shapes from membrane lipids, to associate closely with lipid particles, and the ability to bind to proteins (6). Therefore, if one applies the lipid-carrier initiator hypothesis, Cy-AMPs could provide a source of lipid vesicles by disrupting membrane, if the needed lipid vesicle source is not already provided by seed lipid bodies, and might carry or associate closely with lipid particles or affect lipids near the target protein. Cy-AMPs could act as secondary initiators by also binding to or associating with target protein. Alternatively, the non-specific effect of membrane disruption, could itself promote mixing of lipids with components such as cellular RNA, mixing of lipids with target proteins, mobilization of pre-existing misfolded proteins, or creation of misfolded proteins by the process of membrane disruption and shape change. These factors could promote prion disease in some individuals exposed to Cycads.
The mineral-lipid and the lipid-carrier initiator hypotheses allow us to expand beyond the protein-only model of the pathogenesis of prion and protein-misfolding diseases. These hypotheses provide a potential explanation for a broad array of seemingly disparate factors across multiple prion diseases. There is value in continuing to encourage discussion and in encouraging theories that can explain many aspects of prion diseases in a comprehensive model. Affected individuals and families are served by our willingness to think broadly and creatively about possible models and solutions. With the continued efforts of many, these diseases will one day be understood well and effective interventions will become available.