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.
Keywords: ALS-PDC, Alzheimer disease, amyotrophic lateral sclerosis, methylazoxymethanol, BMAA, formaldehyde, DNA damage, colon cancer
Citation: Spencer P, Fry RC and Kisby GE (2012) Unraveling 50-year-old clues linking neurodegeneration and cancer to cycad toxins: are microRNAs common mediators? Front. Gene. 3:192. doi: 10.3389/fgene.2012.00192
Received: 27 July 2012; Paper pending published: 27 August 2012;
Accepted: 09 September 2012; Published online: 28 September 2012.
Edited by:Peng Jin, Emory University School of Medicine, USA
Reviewed by:Bo Chen, Georgia Health Science University, USA
Copyright: © 2012 Spencer, Fry and Kisby. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Peter Spencer, Global Health Center, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, L356, Portland, 97239 OR, USA. e-mail: firstname.lastname@example.org