Cycad toxins, Helicobacter pylori and parkinsonism: cholesterol glucosides as the common denomenator.
Understanding sporadic cases of age-dependent neurodegenerative diseases such as parkinsonism requires the evaluation of potential environmental factors. Amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC), a neurological disorder in which features of parkinsonism are present and for which no consistent genetic explanation has been found, has been linked to the consumption of cycad (Cycas micronesica). Similarly, epidemiological evidence suggests an association between parkinsonism and gastric ulcer caused by Helicobacter pylori infection. While common immunological and inflammatory changes have been proposed to account for the link between parkinsonism and H. pylori infection, we propose an alternate explanation based on our work on the "cycad theory" of ALS-PDC. Recent experiments in our laboratory have identified several sterol glucosides in cycad that have neurotoxic properties in vitro and that appear to be linked to the development of neurodegenerative disease in vivo. Specifically, mice fed cycad display behavioural symptoms of parkinsonism such as reduced gait length, as well as neuropathological signs such as a loss of striatal dopaminergic (DAergic) terminals and an upregulation of the dopamine D2 receptor. These cycad-derived sterol glucosides are structurally similar to cholesterol glucosides that account for a significant part pf the lipid profile of H. pylori. We hypothesize that cholesterol glucosides arising from H. pylori infection may act as neurotoxins, promoting the degeneration of the DAergic neurons affected in parkinsonism, in a similar reaction to that which is thought to link cycad consumption and ALS-PDC. This hypothesis will be tested in future studies that will include exposing mice to purified sterol or cholestorol glucosides derived from cycad and comparing these mice behaviourally and neuropathologically to ones chronically infected with H. pylori.
Department of Ophthalmology, University of British Columbia, Vancouver, Canada.
J D
JD
Schulz
E L
EL
Hawkes
C A
CA
Shaw
D000690:Amyotrophic Lateral Sclerosis / Q000139:chemically induced / Q000378:metabolism; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000378:metabolism; D029784:Cycas / Q000009:adverse effects; D016481:Helicobacter Infections / Q000378:metabolism*; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D008954:Models, Biological; D010300:Parkinson Disease / Q000378:metabolism* / Q000382:microbiology*; D010947:Plants, Toxic / Q000009:adverse effects
C027578:cholesteryl glucoside; D002784:Cholesterol