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

Abstract

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.

Chronic Exposure to Dietary Sterol Glucosides is Neurotoxic to Motor Neurons and Induces an ALS–PDC Phenotype

“…In support of our preliminary data suggesting neurotoxic actions of cycad's sterol glucosides, other sterols and sterol glucosides have been shown to exhibit toxic properties in animal cells (see Ly et al 2007 for references). In contrast, cholesterol glucoside has been implicated as playing a primary role in the early stages of stress-induced signal transduction in various animal cells, including cultured human fibroblasts (Murakami-Murofushi et al 1997;Kunimoto et al 2000Kunimoto et al , 2002.…”

“…Under the same conditions, the cells showed a significant loss of the heavy neurofilament subunit in the soluble fraction of the cell lysate ( Fig. 1d-e) accompanied by an increase in expression in the beaded processes (Ly et al 2007). …”

“…One answer is that other sources of the putative sterol glucoside neurotoxins must exist in the environment. In relation to this point, the literature shows that phytosterol glucosides and cholesterol glucoside can arise from various sources including diet (Ly et al 2007). For example, soy products containing phytosterols and phytosterol glucosides are major components of the human diet for some populations (Sugiyama and Seki 1991;Kawano et al 2002;Maitani et al 1995;Shimizu et al 1997).…”

“…Some of these cells stained positively for activated caspase-3, indicating apoptosis as a mechanism of cell death. Surviving cells were observed to extend long processes with many "beaded" segments along their length (Ly et al 2007). Treatment with 50 μM of BSSG for 3 days followed by Western blots showed a significant up-regulation of HSP 70, indicative of a cell stress response (Fig.…”

“…Exposure of neural cells to these sterol glucosides also induced a significant up-regulation of protein kinases including PKC and CDK2 and CDK5 . Significantly, in regard to a possible link to ALS-PDC and the neurofibrillary tangles which are a ubiquitous feature of the disease, BSSG also induced increased hyperphosphorylated tau expression in neurons and in NSC-34 motor neuron hybrids (Ly et al 2007). Chronic treatment of organotypic slice preparations at nanomolar concentrations showed that BSSG induced cell death in a dosedependant manner in the spinal cord, hippocampus, and substantia nigra (SN) slice preparations (Wilson et al 2005c; K. Andreassen, C. Mathews; S. Jafri, personal communications, respectively).…”