AUTHOR=Spencer Peter , Fry Rebecca C., Kisby Glen E. TITLE=Unraveling 50-Year-Old Clues Linking Neurodegeneration and Cancer to Cycad Toxins: Are microRNAs Common Mediators? JOURNAL=Frontiers in Genetics VOLUME=3 YEAR=2012 URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2012.00192 DOI=10.3389/fgene.2012.00192 ISSN=1664-8021 ABSTRACT=

Recognition of overlapping molecular signaling activated by a chemical trigger of cancer and neurodegeneration is new, but the path to this discovery has been long and potholed. Six conferences (1962–1972) examined the puzzling neurotoxic and carcinogenic properties of a then-novel toxin [cycasin: methylazoxymethanol (MAM)-β-d-glucoside] in cycad plants used traditionally for food and medicine on Guam where a complex neurodegenerative disease plagued the indigenous population. Affected families showed combinations of amyotrophic lateral sclerosis (ALS), parkinsonism (P), and/or a dementia (D) akin to Alzheimer’s disease (AD). Modernization saw declining disease rates on Guam and remarkable changes in clinical phenotype (ALS was replaced by P-D and then by D) and in two genetically distinct ALS-PDC-affected populations (Kii-Japan, West Papua-Indonesia) that used cycad seed medicinally. MAM forms DNA lesions – repaired by O6-methylguanine methyltransferase (MGMT) – that perturb mouse brain development and induce malignant tumors in peripheral organs. The brains of young adult MGMT-deficient mice given a single dose of MAM show DNA lesion-linked changes in cell-signaling pathways associated with miRNA-1, which is implicated in colon, liver, and prostate cancers, and in neurological disease, notably AD. MAM is metabolized to formaldehyde, a human carcinogen. Formaldehyde-responsive miRNAs predicted to modulate MAM-associated genes in the brains of MGMT-deficient mice include miR-17-5p and miR-18d, which regulate genes involved in tumor suppression, DNA repair, amyloid deposition, and neurotransmission. These findings marry cycad-associated ALS-PDC with colon, liver, and prostate cancer; they also add to evidence linking changes in microRNA status both to ALS, AD, and parkinsonism, and to cancer initiation and progression.