Analysis of neurological disease in four dimensions: insight from ALS-PDC epidemiology and animal models

Shaw, Christopher A.; Wilson, J. M. B.

doi:10.1016/j.neubiorev.2003.08.001

Cited by 22 publications

(19 citation statements)

References 82 publications

(83 reference statements)

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“…Recently Shaw and colleagues, proposed that the causal agents of ALS-PDC and other neurodegenerative disorders are sterol glucosides (Shaw and Wilson, 2003). This is consistent with their inability to observe any behavioral or neuropathological effects when they administered L-BMAA to mice (CruzAguado et al, 2006).…”

Section: In Vivo Studies Of Bmaa Neurotoxicitymentioning

confidence: 74%

“…This data challenge the hypothesis of Shaw and colleagues that sterol glucosides are the causal factors for ALS-PDC and other neurodegenerative diseases Wilson et al, 2002;Shaw and Wilson, 2003). In their most recent review (Ly et al, 2007) they acknowledge the existence of cycad sterol glucosides in many plants, mentioning that their amount in cycad seeds is several orders of magnitude higher compared with other plants and that the critically important point is the dose of exposure.…”

Section: In Vivo Studies Of Bmaa Neurotoxicitymentioning

confidence: 89%

“…Thus the possibility that a considerably subtoxic dose of BMAA was administered to mice must be considered as an explanation for the lack of BMAA toxicity in the Cruz-Aguado et al (2006) study. Shaw and colleagues (Khabazian et al, 2002;Wilson et al, 2002;Shaw and Wilson, 2003;Cruz-Aguado et al, 2006) have suggested that sterol glucosides, particularly β-sitosterol β-Dglucoside (identified as the most toxic component Wilson et al, 2002), campesterol/dihydrobrassicasterol β-D-glucoside and stigmasterol β-D-glucoside, are the neurotoxic components of cycad seeds responsible for ALS-PDC and related neurodegenerative disorders in Guam. To critically discuss this hypothesis, a brief discussion on plant sterols will be given below.…”

Section: In Vivo Studies Of Bmaa Neurotoxicitymentioning

confidence: 99%

“…However, none of them was a clear reproduction of the behavioral and neurodegenerative alterations observed in humans suffering with ALS-PDC and changes observed in postmortem tissues from ALS patients. ALS as well as ALS-PDC are neurodegenerative disorders described strictly in humans but not in other species (Sillevis Smitt and de Jong, 1989;Shaw and Wilson, 2003;Whiting, 1988g). Indeed, Sillevis Smitt and de Jong (1989) reviewed 38 animal models of ALS (including that of Spencer et al, 1987a,b) and spinal muscular atrophies and found all of them wanting in their ability to simulate these human diseases.…”

Section: In Vivo Studies Of Bmaa Neurotoxicitymentioning

confidence: 99%

“…In general, animal models of neurological diseases (including those induced by neurotoxins) are developed to reproduce susceptibility to the human disorder with the assumption that there are common neuropathological changes and shared pathogenetic mechanisms that will improve understanding of the pathogenesis (Sillevis Smitt and de Jong, 1989;Ludolph and Spencer, 1996;Shaw and Wilson, 2003). In the case of ALS and ALS-PDC issues of age-dependency of the disorder and/or a long latent period of expression of the symptoms, the lack of definitive hypotheses for the mechanism(s) of neurotoxicity, and inconsistency of the reported exposures complicate the study of this disease.…”

Section: In Vivo Studies Of Bmaa Neurotoxicitymentioning

confidence: 99%

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Animal models of BMAA neurotoxicity: A critical review

2008

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Section: In Vivo Studies Of Bmaa Neurotoxicitymentioning

confidence: 74%

Section: In Vivo Studies Of Bmaa Neurotoxicitymentioning

confidence: 89%

Section: In Vivo Studies Of Bmaa Neurotoxicitymentioning

confidence: 99%

Section: In Vivo Studies Of Bmaa Neurotoxicitymentioning

confidence: 99%

Section: In Vivo Studies Of Bmaa Neurotoxicitymentioning

confidence: 99%

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Animal models of BMAA neurotoxicity: A critical review

2008

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Environmental neurotoxin‐induced progressive model of parkinsonism in rats

Shen

McDowell

Siebert

et al. 2010

Annals of Neurology

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Objective Exposure to a number of drugs, chemicals or environmental factors can cause parkinsonism. Epidemiologic evidence supports a causal link between the consumption of flour made from the washed seeds of the plant, Cycas micronesica, by the Chamorro population of Guam and the development of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC). Methods We now report that consumption of washed cycad flour pellets by Sprague-Dawley male rats induces progressive parkinsonism. Results Cycad-fed rats displayed motor abnormalities after two to three months of feeding such as spontaneous unilateral rotation, shuffling gait and stereotypy. Histological and biochemical examination of brains from cycad-fed rats revealed an initial decrease in the levels of dopamine and its metabolites in the striatum (STR), followed by neurodegeneration of dopaminergic (DAergic) cell bodies in the substantia nigra pars compacta (SNc). α-synuclein (α-syn; proteinase K-resistant) and ubiquitin aggregates were found in the DAergic neurons of the SNc and neurites in the STR. In addition, we identified α-syn aggregates in neurons of the locus coeruleus and cingulate cortex. No loss of motor neurons in the spinal cord was found after chronic consumption of cycad flour. In an organotypic slice culture of the rat substantia nigra and the striatum, an organic extract of cycad causes a selective loss of DA neurons and α-synuclein aggregates in the substantia nigra. Interpretation Cycad-fed rats exhibit progressive behavioral, biochemical, and histological hallmarks of parkinsonism, coupled with a lack of fatality.

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Novel environmental toxins: Steryl glycosides as a potential etiological factor for age‐related neurodegenerative diseases

Ly¹,

Singh²,

Shaw³

2006

J of Neuroscience Research

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Amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC) is a unique neurodegenerative disease found on the island of Guam. This disease presents as a spectrum of neurological disorders characterized by features of ALS, parkinsonism, dementia, or a combination. The strongest epidemiological link has been to the consumption of the seeds from the cycad plant that purportedly contained a neurotoxin. Mice fed washed cycad flour show signs that mimic ALS-PDC, which include progressive deficits in motor, cognitive, and olfactory functions associated with neuron loss in the spinal cord, nigrostriatal system, cortex, hippocampus, and olfactory bulb. Through a series of chemical extractions of washed cycad flour, we identified steryl glycoside molecules as bioactive molecules that are neurotoxic in culture and in mice. A detailed review of this class of molecule revealed that the molecules are abundant in the environment, particularly in plants and bacteria. Lipid analysis showed that some bacteria that are associated with some forms of neurodegenerative disorders have the capacity to synthesize steryl glycosides. Furthermore, certain steryl glycosides have been found to be a cell stress mediator and may have some immunomodulary effects. We hypothesize that steryl glycosides are putative neurotoxins involved in the etiopathogenesis of several age-related neurodegenerative disorders.

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Analysis of neurological disease in four dimensions: insight from ALS-PDC epidemiology and animal models

Cited by 22 publications

References 82 publications

Animal models of BMAA neurotoxicity: A critical review

Animal models of BMAA neurotoxicity: A critical review

Environmental neurotoxin‐induced progressive model of parkinsonism in rats

Novel environmental toxins: Steryl glycosides as a potential etiological factor for age‐related neurodegenerative diseases

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