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.