ALS parkinsonism-dementia complex (ALS-PDC) is a neurological disease that can present as classical ALS, an Alzeheimer's-like disorder with associated parkinsonism features, or a combination. It is a cluster of age-dependent neurodegenerative disorders, representing the only widely acknowledged such cluster and may offer vital clues to the etiology of related disorders. We have successfully modeled the disease by feeding washed cycad flour to adult mice, which develop behavioral and histopathological deficits resembling ALS-PDC. The ability to model the disease allows us to ask fundamental questions of great potential impact for related disorders: Which environmental toxins and genetic susceptibilities contribute to neurodegeneration? What is the time course of the behavioral and pathological deficits from initial expo- sure until behavioral end state? How does age affect disease development and progression? Finally, based on the above, can we design prophylactic and early treatment strategies to prevent further neurode- generation? Using our model of ALS-PDC, we will address the crucial questions of (1) neurodegeneration time-line and (2) the impact of neurotoxins as a function of age. To probe these questions, adult male CD-1 mice will be fed washed cycad or the isolated putative cycad toxins, variant steryl glucosides. A detailed time-line of behavioral, morphological, and biochemical events will be studied from initial exposure through to an end state for both groups. To further examine crucial events in the neurodegeneration cascade, neural cells will be examined in a tissue culture preparation during and following exposure to steryl glucosides. The proposed age effects study will examine two aspects: cycad neurotoxin-induced behavioral and pathological effects as a function of age over a span of 1 to 18 months. In a second series of experiments, we will determine if an early exposure to cycad toxins can exacerbate a late adult expo- sure. These data will provide therapeutic targets to prevent or halt the progression of neurodegeneration.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Gubitz, Amelie
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University of British Columbia
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V6 1-Z3
Marler, Thomas E; Shaw, Christopher A (2010) Distribution of free and glycosylated sterols within Cycas micronesica plants. Sci Hortic (Amsterdam) 123:537
Panov, Alexander; Kubalik, Nataliya; Brooks, Benjamin R et al. (2010) In vitro effects of cholesterol ýý-D-glucoside, cholesterol and cycad phytosterol glucosides on respiration and reactive oxygen species generation in brain mitochondria. J Membr Biol 237:71-7
Shen, Wei-Bin; McDowell, Kimberly A; Siebert, Aubrey A et al. (2010) Environmental neurotoxin-induced progressive model of parkinsonism in rats. Ann Neurol 68:70-80
Marler, Thomas E; Snyder, Laura R; Shaw, Christopher A (2010) Cycas micronesica (Cycadales) plants devoid of endophytic cyanobacteria increase in beta-methylamino-L-alanine. Toxicon 56:563-8
Marler, Thomas E; Shaw, Christopher A (2009) Free and glycosylated sterol bioaccumulation in developing Cycas micronesica seeds. Food Chem 115:615
Shaw, Christopher A; Petrik, Michael S (2009) Aluminum hydroxide injections lead to motor deficits and motor neuron degeneration. J Inorg Biochem 103:1555-62
Marler, Thomas E; Shaw, Christopher A (2009) Phenotypic Characteristics as Predictors of Phytosterols in Mature Cycas micronesica Seeds. HortScience 44:725-729
Snyder, Laura R; Cruz-Aguado, Reyniel; Sadilek, Martin et al. (2009) Parkinson-dementia complex and development of a new stable isotope dilution assay for BMAA detection in tissue. Toxicol Appl Pharmacol 240:180-8
Lee, Grace; Chu, Tony; Shaw, Christopher A (2009) The primary locus of motor neuron death in an ALS-PDC mouse model. Neuroreport 20:1284-9
Shaw, Christopher A; Hoglinger, Gunter U (2008) Neurodegenerative diseases: neurotoxins as sufficient etiologic agents? Neuromolecular Med 10:1-9

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