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Cycad Genotoxin Methylazoxymethanol (MAM) Modulates Cellular Pathways Involved in Cancer and Neurodegenerative Disease

ABSTRACT: Methylazoxymethanol (MAM), the genotoxic metabolite of the cycad azoxyglucoside cycasin, induces genetic alterations in bacteria, yeast, plants, insects and mammalian cells, but adult nerve cells are thought to be unaffected. We show that the brains of young adult mice treated with a single systemic dose of MAM display DNA damage (O6-methylguanine lesions) that peaks at 48 hours and decline to near-normal levels at 7 days post-treatment. By contrast, at this time, MAM-treated mice lacking the gene encoding the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT), showed persistent O6-methylguanine DNA damage. The DNA damage was linked to cell-signaling pathways that are perturbed in cancer and neurodegenerative disease. These data are consistent with the established carcinogenic and developmental neurotoxic properties of MAM in rodents, and they support the proposal that cancer and neurodegeneration share common signal transduction pathways. They also strengthen the hypothesis that early life exposure to the MAM glucoside cycasin has an etiological association with a declining, prototypical neurodegenerative disease seen in Guam, Japan, and New Guinea populations that formerly used the neurotoxic cycad plant for medicine and/or food. Exposure to environmental genotoxins may have relevance to the etiology of related tauopathies, notably, Alzheimer’s disease, as well as cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE26600 | GEO | 2013/01/10

SECONDARY ACCESSION(S): PRJNA136203

REPOSITORIES: GEO

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Project description:Amyotrophic lateral sclerosis (ALS) is a rapidly progressive, fatal neurodegenerative disorder, characterized by selective loss of motor neurons (MNs). A number of causative genetic mutations underlie the disease, including mutations in the fused in sarcoma (FUS) gene, which can lead to both juvenile and late onset ALS. Although ALS results from MN’s death, there is evidence that dysfunctional glial cells, including oligodendroglia, contribute to neurodegeneration. Here, we used human induced pluripotent stem cells (hiPSCs) with a FUSR521H or a FUSP525L mutation and their isogenic controls to generate oligodendrocyte progenitor cells (OPCs) by inducing SOX10 expression from a TET-On SOX10 cassette as described previously in our lab. Mutant and control iPSC differentiated efficiently into OPCs. RNA sequencing identified a myelin sheath-related phenotype in mutant OPCs. Subsequent lipidomics studies demonstrated defects in myelin lipids, with a reduction of phospholipids in mutant OPCs. Among them, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) are the most two abundant phospholipid in mammalian cells and regulate the mitochondria-associated ER membrane (MAM) integrity. Interestingly, FUSR521H mutant OPCs displayed a decrease in the PC/PE ratio, known to be associated with maintaining membrane (mitochondria) integrity. Proximity ligation assay further indicated that MAM was diminished in mutant OPCs. Moreover, mutant OPCs displayed stronger activation of unfolded protein response markers, a hallmark of increased susceptibility to endoplasmic reticulum (ER) stress, when exposed to thapsigargin, and exhibited impaired mitochondrial respiration and reduced Ca2+ signaling from ER Ca2+ stores. Taken together, these results demonstrate that FUS mutant OPCs display defects in lipid metabolism associated with MAM disruption manifested by impaired mitochondrial metabolism with increased susceptibility to ER stress and suppressed physiological Ca2+ signaling events.

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Cycad Genotoxin Methylazoxymethanol (MAM) Modulates Cellular Pathways Involved in Cancer and Neurodegenerative Disease

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