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Neuromolecular Med. 2008 ; 10(1): 1. doi:10.1007/s12017-007-8016-8.

Neurodegenerative Diseases: Neurotoxins as Sufficient Etiologic

Agents?

Christopher A. Shaw and

Department of Ophthalmology, University of British Columbia, Vancouver, BC, Canada
Department of Experimental Medicine and the Neuroscience Program, University of British
Columbia, Vancouver, BC, Canada
Günter U. Höglinger
Experimental Neurology, Philipps University, 35033 Marburg, Germany

Abstract
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A dominant paradigm in neurological disease research is that the primary etiological factors for
diseases such as Alzheimer’s (AD), Parkinson’s (PD), and amyotrophic lateral sclerosis (ALS) are
genetic. Opposed to this perspective are the clear observations from epidemiology that purely genetic
casual factors account for a relatively small fraction of all cases. Many who support a genetic etiology
for neurological disease take the view that while the percentages may be relatively small, these
numbers will rise in the future with the inevitable discoveries of additional genetic mutations. The
follow up argument is that even if the last is not true, the events triggered by the aberrant genes
identified so far will be shown to impact the same neuronal cell death pathways as those activated
by environmental factors that trigger most sporadic disease cases. In this article we present a
countervailing view that environmental neurotoxins may be the sole sufficient factor in at least three
neurological disease clusters. For each, neurotoxins have been isolated and characterized that, at least
in animal models, faithfully reproduce each disorder without the need for genetic co-factors. Based
on these data, we will propose a set of principles that would enable any potential toxin to be evaluated
as an etiological factor in a given neurodegenerative disease. Finally, we will attempt to put
environmental toxins into the context of possible genetically-determined susceptibility.

Keywords
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Neurological disease cluster; Atypical parkinsonism; Parkinsonism-dementia complex; ALS;

Progressive subranuclear palsy; Guam; Guadeloupe; Cycad; Annonacin; Sterol glucosides ; MPTP;
Environmental toxins

Introduction
The notion that numerous human diseases arise primarily due to genetic abnormalities is widely
accepted. The technical success of the human genome project has served to strengthen this
view, albeit without providing much insight into post-sequencing mechanisms of action. In
turn, this notion is widely touted in the media, leading to a general perception by the lay public
that a widespread genetic basis for human disease causality is an established fact. The general

© Humana Press Inc. 2007

C. A. Shaw Neural Dynamics Research Group, 828 W. 10th Ave, V5Z 1L8, Vancouver, BC, Canada, e-mail: cashawlab@gmail.com.
Christopher A. Shaw and Günter U. Höglinger are the co-primary authors of this article.
 Shaw and Höglinger Page 2

perspective on neurological diseases tends to be similar. In part, this view is bolstered by

neurological disorders such as Huntington’s disease that are clearly of genetic origin. The
successful identification of mutations associated with familial forms of Alzheimer’s disease
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(AD), Parkinson’s disease (PD), and amyotrophic lateral sclerosis (ALS) similarly supports
the notion of genetic etiology. Whatever individual scientists may say privately, it is the
‘‘gene’’ perspective that sends the vast bulk of extramural research funding—both public and
private—into studies devoted to genetic rather than toxin etiologies.

In spite of this, epidemiology tells a somewhat different story in regard to sporadic cases of
the age-dependent neurodegenerative disorders. Although estimates vary, in no case do the
known gene mutations account for more than 10% for any of these diseases overall We cannot,
however, rule out future discoveries that could serve to bring larger fractions of the sporadic
forms of each disease into the genetic causality fold. Similarly, it is undeniable that the cell
death cascades evoked by any form of genetic abnormality (i.e. gene mutations, deletions or
duplications) could be identical to those triggered in other ways, for example by neurotoxins.

In the following review, we will summarize the evidence for a neurotoxin etiology in three
well-established clusters of neurological disease and demonstrate that for each an animal model
using the putative neurotoxin can faithfully reproduce the disease state. These outcomes argue
in favor of such toxins being the sole necessary and sufficient condition for at least these disease
clusters.
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The clusters we will consider are the following: (1) The type of parkinsonism associated with
the accidental use of MPTP by recreational drug users; (2) atypical parkinsonism of
Guadeloupe in the French Antilles; (3) The separate and combined phenotypes of ALS and
parkinsonism dementia of the Western Pacific, with a focus on the most studied of these among
the Chamorro population of Guam. From these examples, we will try to derive basic principles
to serve in the hunt for environmental toxins associated with other forms of sporadic
neurodegenerative disease. Last, we will consider the combined effects of modifier genes and
environmental toxins.

Environmental Determinants of Neurological Disease: Three Clusters

MPTP-Induced Parkinsonism
In 1983, Langston et al. reported the occurrence of an akinetic rigid syndrome responsive to
Levodopa resembling the clinical features of PD in seven individuals after intravenous injection
of an illicit synthetic heroin analog that contained high amounts of the by-product 1-methyl 4
—phenyl 1,2,3, 6-tetradhydropyridine (MPTP) (Langston et al. 1983; Ballard et al. 1985).
Subsequent studies demonstrated that systemic injection of MPTP into non-human primates
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(Langston et al. 1984a) and mice (Ricaurte et al. 1987) induced an irreversible, selective loss
of dopaminergic neurons in the substantia nigra (SN), thus reproducing the main
neuropathological hallmark of PD. MPTP is a highly lipophilic molecule (Riachi et al. 1989)
and crosses the blood–brain-barrier in a matter of seconds after systemic administration
(Markey et al. 1984). Within the brain, MPTP is rapidly converted to the hydrophilic metabolite
1-methyl-4-phenylpyridinium ion (MPP+) (Heikkila et al. 1984; Langston et al. 1984b) which
is not lipophilic enough to cross biomembranes spontaneously (Riachi et al. 1989). The
demonstration that an inhibition of the conversion of MPTP to MPP+ by monoamine oxidase
B prevents MPTP-neurotoxicity, clearly identified MPP+ as the active toxic principle (Heikkila
et al. 1984; Langston et al. 1984b). Further work demonstrated that the cellular specificity of
MPTP for dopaminergic neurons resulted from the accumulation of MPP+ through uptake by
the dopamine transporter (Javitch et al. 1985; Ricaurte et al. 1985; Bezard et al. 1999). Within
the cell, MPP+ accumulates in the mitochondrial matrix (Ramsay and Singer 1986; Davey et
al. 1992) where it impairs respiration by inhibiting complex I (NADH-ubiquinone

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oxidoreductase) of the electron transport chain (Nicklas et al. 1985; Singer et al. 1987). The
downstream mechanisms of MPP+–induced complex I inhibition that lead ultimately to
neuronal cell death and parkinsonism are reviewed elsewhere (Dauer and Przedborski 2003;
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Dawson and Dawson 2003).

The relevance of MPTP-induced parkinsonism as a model for sporadic PD comes from the
demonstration of a similar impairment of mitochondrial complex I in PD (Schapira et al.
1989; Schapira et al. 1990; Mann et al. 1992; Abou-Sleiman et al. 2006; Keeney et al. 2006).
The principal differences between PD and MPTP-induced parkinsonism in the routinely used
acute and subacute intoxication protocols are the lack of chronic progression of
neurodegeneration in experimental animals and the absence of formation of typical Lewy
bodies, the protein-aceous inclusion bodies that are characteristic of PD and related disorders
(Forno et al. 1993). Recent experimental approaches utilizing chronic MPTP administration
protocols appear to demonstrate that MPTP-induced parkinsonism is even closer to ‘‘classical’’
PD in its absence of extra-nigral pathology (Fornai et al. 2005). At the same time, more detailed
studies of the timecourse of PD pathology appears to suggest that a more widespread impact
on the CNS occurs (Braak et al. 2004). MPTP may thus reflect an extremely selective form of
a disease that may have multiple manifestations.

Guadeloupean Atypical Parkinsonism

The inhabitants of Guadeloupe, a French Caribbean island, experience an unusually high
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prevalence of atypical parkinsonism (Caparros-Lefebvre and Elbaz 1999; Caparros-Lefebvre

et al. 2006; Lannuzel et al. 2007) which exceeds that observed in European or North American
populations. Approximately one-third of the parkinsonian patients present with classical PD,
one-third with a clinical manifestation resembling progressive supranuclear palsy (PSP), and
one-third have an undetermined form of parkinsonism (Caparros-Lefebvre and Elbaz 1999;
Caparros-Lefebvre et al. 2002; Lannuzel et al. 2007). In three of the patients with PSP-like
clinical symptoms who have come to autopsy, neuropathological alterations consistent with
PSP were found (Caparros-Lefebvre et al. 2002). The absence of Mendelian inheritance or of
mutations in the MAPT or α-synuclein genes, as well as the ethnic heterogeneity of the affected
population argues against a genetic causality (Caparros-Lefebvre and Elbaz 1999; Caparros-
Lefebvre et al. 2002, 2006; Lannuzel et al. 2007). In contrast, the geographical clustering is
consistent with an environmental etiology.

A case-control study (Caparros-Lefebvre and Elbaz 1999) linked atypical parkinsonism on

Guadeloupe to the consumption of fruit and medicinal preparations of the leaves of plants of
the Annonaceae family, in particular Annona muricata (soursop, corossol) the predominant
Annonaceae on Guadeloupe. Associations between the consumption of Annonaceae and
atypical parkinsonism have also been reported in New Caledonia (Angibaud et al. 2004) and
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in patients of Caribbean origin in living in London (Chaudhuri et al. 2000). These associations
in widely separated populations with genetically distinct backgrounds further support the
hypothesis that toxic compounds contained in Annonaceae may be responsible for the observed
neurodegenerative syndrome.

Acetogenins and alkaloids are the two major groups of candidate toxins contained in plants
from the Annonaceae family. In vitro, acetogenins are toxic to neurons at concentrations in the
nanomolar range, whereas micromolar concentrations of the alkaloids were necessary to
produce toxic outcomes (Lannuzel et al. 2002; Lannuzel et al. 2003). For this reason,
acetogenins have received greater attention in recent years. Acetogenins penetrate into cells
by passive diffusion because of their lipophilic character rather than servng as a substrate for
the dopamine transporter (Lannuzel et al. 2003). These observations explain why these
compounds are equally toxic to various dopaminergic as well as non-dopamine containing
neurons (Lannuzel et al. 2003), acting in both as potent inhibitors of mitochondrial complex I

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(Degli Esposti 1998). Annonacin, the most abundant acetogenin in Annona muricata, inhibits
complex I activity with an IC50 of about 30 nM and kills neurons by ATP-depletion. It is about
50 times more toxic to dopaminergic neurons and 2000 times more toxic to non-dopaminergic
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neurons than MPP+ (Lannuzel et al. 2003). When administered intravenously to rats for 28
days, annonacin enters the brain parenchyma, decreases brain ATP levels and induces
pronounced and widespread neurodegeneration in basal ganglia and brainstem nuclei;
hippocampus, cerebellum, and cerebral cortex are only moderately affected (Champy et al.
2004). These outcomes mimic the distribution of brain lesions seen in patients with atypical
parkinsonism of Guadeloupe (Caparros-Lefebvre et al. 2002). Quantification of the acetogenin
content in A. muricata fruits and products demonstrates that an adult who consumes one fruit
or can of nectar per day will ingest in 1 year the amount of annonacin relative to body weight
that induces brain lesion in rats (Champy et al. 2005). It is noteworthy that the chronic systemic
administration to rats of rotenone, another plant-derived, lipophilic, and highly potent complex
I inhibitor, produces the identical pattern of mitochondrial energy impairment and
neurodegeneration (Höglinger et al. 2003). In addition, rotenone-treated rats also develop a
cerebral tauopathy with ultrastructural and molecular features resembling those found in PSP-
brains (Höglinger et al. 2005). Annonacin is also capable of inducing somatodendritic
redistribution of abnormal tau protein in cultured neurons (Escobar-Khondiker et al. 2007).
These observations strengthen the hypothesis that natural lipophilic complex I inhibitors, such
as the acetogenins contained in annonaceous plants, are capable of inducing atypical
parkinsonism of the PSP-type. The concept that mitochondrial dysfunction plays a role in the
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etiology of PSP-like syndromes is further supported by the observation that cybrid cells
containing mitochondria from PSP patients have defective mitochondrial function (Swerdlow
et al. 2000; Albers et al. 2001).

ALS-Parkinsonism Dementia Complex (ALS-PDC) of the Western Pacific

A high incidence of what at first appeared to be a classical form of ALS was identified by
American Navy doctors among the Chamorro people of Guam shortly after World War II
(Zimmerman 1945). Later clinical characterization (Kurland and Mulder 1954; Kurland et al.
1961) confirmed a near epidemic level of the disorder. A second disease with a similarly high
incidence was soon added to the emerging picture. This was an atypical form of parkinsonism
that presented with dementia and was named parkinsonism dementia complex (PDC) (Hirano
et al. 1961). Marked similarities to PSP have since been noted (Steele et al. 2002), both in the
abnormal expression of abnormal tau protein and in neuronal loss in regions not associated
with classical PD. The spectrum of neurological disorders of both types was collectively
referred to as ALS-PDC. Most cases were predominantly either ALS or PDC; however, there
was notable overlap with about 7% of the patients suffering from both disorders (Kurland and
Mulder 1954). A familial susceptibility to disease was noted, however affected members within
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one family could exhibit either of the separate disorders.

Disease incidence for ALS on Guam has declined dramatically and now is only marginally
higher than the North American average. PDC appears to have declined in recent years, but
remains higher than for PD in North America (Galasko et al. 2002). Controversy still exists
concerning the extent of the decline (D. Galasko personal communication). Apparently
pathologically similar forms of ALS-PDC have been described elsewhere in the Western
Pacific, notably in Irian Jaya (western New Guinea) (Gajdusek and Salazar 1982) and the Kii
Peninsula of Honshu Island in Japan (Kurland 1972). Histologically, both Guamanian ALS
and PDC are characterized by the abundance of neurofibrillary tangles (NFT) of abnormal tau
protein whose presence in Guamanian ALS was considered to mark a significant deviation
from the classical form. However, the perception that ALS pathology does not involve
abnormal tau expression may be changing with recent descriptions of tangles found in the
temporal lobes of cognitively impaired ALS patients (Strong et al. 1999, 2006; Strong 2003).

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In a similar manner, the presence of NFT, together with the neuronal loss outside the nigro-
striatal pathway observed in PDC, resembles both PSP and Guadeloupean atypical
parkinsonism. The dementia associated with PDC was thought by Kurland and others (Kurland
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1972) to resemble AD in a number of aspects, albeit with an underrepresentation of amyloid-

β depositions (Winton et al. 2006), possibly making it more like frontotemporal dementia
(FTD) than AD (Galasko et al. 2002).

The increased susceptibility to ALS-PDC development in some families suggested the

influence of modifier genes, but no clear evidence of inheritance of a disease causing mutation
has since emerged (Trojanowski et al. 2002; Hermosura et al. 2005). Instead, the strongest
epidemiological data have historically supported an environmental factor(s) as causal to the
disease. The strong epidemiological link was recently reconfirmed (Borenstein et al. 2007).

Various environmental hypotheses have been put forward over the years ranging from
deficiencies in calcium and magnesium in ground water (Gajdusek and Salazar 1982) to the
presence of toxic compounds contained in the gametophyte of the local variety of cycad tree
(Cycas micronesica). Consumption of flour made from cycad seeds, termed fadang in
Chamorro, has been a recognized feature of Chamorro culture for generations (Whiting
1963), but has declined considerably since the war.

Cycad gametophytes contain various known toxins, including the amino sugar cycasin whose
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active principle is the hepatotoxin methylazoxymethanol (MAM) as well as the free amino
acids β-oxalyoamino alanine (BOAA) and β-methylamino alanine (BMAA). MAM ingestion
in animals does not induce neural outcomes resembling ALS-PDC (Kurland et al. 1961) or
indeed show any pronounced neural impact in adult animals. BOAA, an AMPA receptor
agonist, has been linked to neurolathyrism (Spencer and Schaumburg 1983), but the features
of this disease do not closely resemble those of ALS-PDC. BMAA appears to activate both
NMDA and AMPA receptors (Weiss et al. 1989; Rao et al. 2006) in vitro, but does not generate
ALS-PDC- like features in vivo (Cruz-Aguado et al. 2006). In this regard, Spencer et al.
(1987) had originally suggested that BMAA in high doses could do so, but the behavioral
deficits and apparent pathological outcomes observed by these investigators were neither
consistent with ALS-PDC nor were they permanent once BMAA treatment ended. Later studies
failed to replicate even these minimal outcomes (Perry et al. 1989; Duncan et al. 1990; Cruz-
Aguado et al. 2006). An additional barrier to any of the above water-soluble toxins as etiologic
agents of ALS-PDC is that all elute as the seeds are washed in the traditional methods of
Chamorro cycad flour preparation (Duncan 1991; Wilson et al. 2002).

More recently, evidence for additional neurotoxins contained in cycad seeds from Guam has
emerged. In vivo feeding of washed cycad flour (lacking any of the water-soluble toxins
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described above) to adult male mice gives rise to a progressive neurological disorder that
recreates much of the spectrum of ALS-PDC. In particular, cycad-fed mice display motor
deficits consistent with ALS and parkinsonism, including ALS-PDC olfactory and late stage
cognitive deficits (Wilson et al. 2002). Magnetic imaging and histological examination reveal
a decreased volume and neuron losses in spinal cord, SNpc, olfactory bulb, hippocampus, and
some regions of the cortex (Wilson et al. 2002, 2004, 2005). The same regions show evidence
of astrogliosis and/or microglial proliferation (Wilson et al. 2006).

Similar cycad samples fed to adult male rats generate an apparently pure parkinsonism
phenotype. At the onset of behavioral symptoms, cycad-fed rats initially unilaterally rotate,
with corresponding losses of tyrosine hydroxylase activity and neurons in SNpc and dopamine
terminals in the striatum. Both lesions are on the contralateral side to the direction of rotation
(Valentino et al. 2006). Once initiated, the disorder continues to progress in the absence of
continued exposure to cycad neurotoxins with all of the rats showing a later behavioral stage

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characterized by freezing. This stage corresponds to the emergence of bilateral SNpc and
striatal lesions.
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The isolation of bioactive molecules from washed cycad flour suggests that at least three sterol
glucoside variants are, individually or in combination, the active toxic principle (Khabazian et
al. 2002). Sterol glucosides of various types are known to have neurotoxic properties (Ly et
al. 2006) and due to their highly lipophilic nature may easily access the nervous system. The
largest fraction of sterol glucosides in cycad is usually β-sitosterol β-D glucoside (BSSG),
however the absolute amounts and ratios of the different sterol glucosides can vary
considerably between batches of cycad seeds. These variations likely arise due to differences
in the season harvested, locale, and, most crucially, seed age (Marler et al. 2005a): Cycad sterol
glucoside concentrations, especially in young seeds, appear to be considerably higher than for
most other plants studied to date (Marler et al. 2005b).

The identified cycad sterol glucosides are neurotoxic to primary neuronal and astroglial
cultures (Khabazian et al. 2000; Khabazian et al. 2002) as well as to an motor neuron-derived
cell line (NSC-34) (Ly et al. 2007; Ly and Shaw 2007). Studies using organotypic slices of
spinal cord, SNpc/striatum, or hippocampus with BSSG in nanomolar concentrations or a
cholesterol glucoside all show significant neuronal death over a period of days to weeks (S.
Jafri, K. Andreassen, and C. Mathews, personal communications). Synthetic BSSG fed to mice
at concentrations approximating those measured in cycad flour, gives rise to behavioral deficits
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consistent with an ALS-like phenotype with concomitant progressive motor neuron loss in
spinal cord and later cell loss in the striatum (Wilson et al. 2006; Tabata et al. 2007). These
outcomes occur even in the absence of further exposure to BSSG.

The data from the ALS-PDC models cited above strongly supports the interpretation that
several water insoluble neurotoxic factors in cycad seeds from Guam are indeed causal to the
human disease in its various forms. Whether or not the identified sterol glucosides are alone
responsible for the all of the pathological outcomes observed in the animal experiments using
cycad seed flour is still uncertain.

A Comparison of Guadeloupean Atypical Parkinsonsim and ALS-PDC

There is considerable overlap in observed features between the parkinsonism observed in
Guadeloupean atypical parkinsonsim and ALS-PDC. For example, both can be defined as
sporadic neurodegenerative tauopathies and both show some resemblance to PSP by involving
CNS regions outside the nigro-striatal system. The differences in presentation may reflect the
strong possibility that different neurotoxins, as cited in the previous sections, are involved.
However, we cannot currently rule out the possibility that both C. micronesica and
Annonaceae may contain significant concentrations of both sterol glucosides and acetongenins.
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We have also noted elsewhere the structural similarity of the sterol glucosides to at least one
of the toxic alkaloids, reticuline, found in Annonaceae (Slow et al. 2003).

Criteria for the Identification of Environmental Factors as Causative Agents

in Neurodegenerative Diseases
Based on the experimental approaches utilized to study ALS-PDC, Guadeloupean atypical
parkinsonism, as well as MPTP-induced parkinsonism, we propose that the following criteria
could be used to guide a search to identify and validate putative neurotoxins involved in the
etiology of sporadic neurodegenerative disease. These criteria are:
1. Epidemiological validity: Clinical and pathological evidence consistent with disease
segregation by exposure to the putative neurotoxin must exist in individuals or
particular human populations;

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2. Agent identification: Isolation, purification, and structural determination of the

putative neurotoxin must be accomplished. The neurotoxin must be able to gain access
to the CNS under realistic conditions, e.g., ingestion or inhalation, and must, in
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addition, exhibit plausible dosages and exposure periods;

3. Experimental modeling in vivo: Exposure of experimental animals to the neurotoxin
must recreate the human disease, both behaviorally and histopathologically;
4. Extinction by prevention: The prevention of exposure to the neurotoxic agents
should serve to eradicate the disease.

Environment-Gene Interactions and Neurodegenerative Disease

The last few years have seen an impressive increase in the knowledge of the genetic
contribution to the etiology of some neurodegenerative disorders. For example, mutations in
a single gene have been identified as being causative for Huntington’s disease. A transgenic
animal model expressing this mutation has been developed that closely mimics the disease,
thus allowing researchers to study potential neuroprotective interventions.

Most neurodegenerative disorders, however, are far more complex. In both AD and PD, for
example, only a small percentage of cases are inherited in a simple Mendelian fashion, the vast
majority remaining in the sporadic category. A similar situation exists in regard to ALS.
Nonetheless, the identification and experimental study of the genes involved in the inherited
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forms of neurodegenerative diseases have allowed researchers to identify molecular pathways

leading to neurodegeneration and the hope remains that these will turn out to be the same as
those evoked in sporadic disease.

In AD for example, all gene defects identified so far appear to drive a common metabolic
pathway that involves the production, processing, or clearance of amyloid protein (Mayeux
2006). Such observations can guide the search for neurotoxins that affect, directly, or indirectly
the same pathway. In contrast, in PD the inherited forms of the disease do not map to a solitary
pathway. Similarly, in ALS, gene-evoked neuropathological cascades seem more likely to
involve multiple pathways. Thus for PD and ALS, the notion that identifying gene mutations
will necessarily lead to any clearer understanding of the sporadic forms of the disease is not
necessarily correct. Insofar as it is not correct, the best justification for genetic studies in these
disorders is that the events triggered may converge on common downstream targets to give
clinically and pathologically identical outcomes.

Putting Toxin-Gene Synergies into Perspective

The above discussion of the relative impact of environmental neurotoxins versus genetic factors
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in neurological disease leads to the following conclusions: Although various gene variants/
mutations can induce a percentage of overall cases of ALS, PD, and AD, this fraction is not
large. Nor is it absolutely clear even in such cases that the aberrant genes alone are solely causal
to the disease since potential environmental factors acting in synergy cannot be discounted.
This is well illustrated by the current failure of PD transgenetic models to generate the full
pathological spectrum of the disease (Emborg 2004). The same lack of effect holds for the
animal model of the ALS2 mutation to the protein alsin (Devon et al. 2006). Gene proponents
often point to the success of the mSOD model of the various mutations involved in some
familial forms of ALS in which homozygous mice and rats develop a rapidly fatal motor neuron
loss and display many of the clinical and pathological features seen in human ALS. In this
view, these data are strong evidence for a strict genetic etiology. However, it must be noted
that high levels of expression of the mSOD mutation also impact a variety of other areas of
CNS, including the SNpc, striatum, and hippocampus, suggesting that the intensity of the insult

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provided by the mutation is very great (Petrik et al. 2007). In contrast, low expressing mSOD
mice show relatively minor or late expressing pathological outcomes (Julien and Kriz 2006).
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If many of the demonstrated mutations are alone insufficient to re-create the human
neurological disease in animal models, what are the chances that environmental factors alone
do so? The models discussed above—as well as various others not considered in this review
—clearly show that such potential exists. Cycad and Annona neurotoxins can be linked
epidemiologically to ALS-PDC on Guam and elsewhere, and atypical parkinsonism in various
locations, respectively. The problem here, however, is one of universality: Outside of these
rare clusters of disease, can worldwide cases of ALS, PD/parkinsonism, or AD be linked to
either group of potential toxins? The presence of various sterol glucosides from a variety of
sources suggests that these may to some extent satisfy a criterion of universality (Ly et al.
2007). The same could be true of the Annonaceous toxins, but more likely reflect not a specific
molecule but rather a number of molecules of different types that share common toxic
mechanisms of action.

Thus, although such toxins—related by type or mechanism of action—could be causal to

neurological diseases, a central question remains unanswered: Why are there not more clusters
of neurological disease? One answer may be that although such toxins can kill neurons in the
CNS at sufficient concentrations, such fatal concentrations may be rare, only occurring in
places such as Guam or Guadeloupe. Hence, the causal toxins might be ubiquitously
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distributed, but the exposure for most people may occur at concentrations too low to induce
disease. If so, then the obvious exception might be those who share some genetic susceptibility
that influences toxin accessibility, transport, or degradation. Numerous examples of such
genetic susceptibility factors exist, one of the most widely known that of the polymorphisms
in the cholesterol transport gene apoE. In regard to the latter, cycad toxicity in mice seems to
be in part regulated by apoE variants in a manner than appears to reflect the risk of ALS and
AD in humans (Bédlâck et al. 2000; Wilson et al. 2005; Mayeux 2006).

These speculations lead to a view that is rapidly gaining support, namely that environmental
and genetic factors must interact to cause sporadic neurological diseases. This last
consideration, in addition to toxin only or gene only etiologies is illustrated in the schematic
of Fig. 1. It is also increasingly likely that toxins may directly alter gene function: Epigenetic
modifications of chromatin leading to changes in DNA methylation may be a crucial factor in
toxin-gene interactions (D’Alessio and Szyf 2006).

All of the above speculation is open to experimental scrutiny. It seems to us that an urgent
future priority in the field will be to conduct a systematic exploration of the interactions
identified neurotoxins and mutations. From such studies may come the ultimate answer and
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hope for prophylaxis to sporadic neurodegenerative disease.

Acknowledgments
This work was supported by the US Army Medical Research and Materiel Command (#DAMD17-02-1-0678), Scottish
Rite Charitable Foundation of Canada, and the Natural Science and Engineering Research Council of Canada
(NSERC), and NINDS to CAS and European Union Grant LSHM-CT-2003-503330 to GUH. The authors thank
Michael Petrik, Dr. Reyniel Cruz-Aguado and Dr. Denis Kay for helpful suggestions and commentary.

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Fig. 1.
Schematic representation of different modes of putative gene-environment interactions in the
etiology of a neurodegenerative disease ‘‘X’’, as defined by a unique clinical or
neuropathological phenotype. (a) One of several genetic mutations may be the sole trigger the
disease. (b) One of several environmental toxins may be the sole trigger of the disease. (c) One
or several genetic mutations may be the prime trigger of the disease, the penetrance or severity
of which may be modified by environmental factors. (d) One or several environmental toxins
may be the prime trigger of the disease, the penetrance or severity of which may be modified
by genetic factors. (e) Environmental and genetic factors, both being too weak individually to
trigger the disease, may be required, interacting in a synergistic manner to trigger the disease
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