Unraveling 50-yearold clues linking neurodegeneration and cancer to cycad toxins: Are microRNAs common mediators?

Peter Spencer, Rebecca C. Fry, Glen E. Kisby

Research output: Contribution to journalArticle

20 Scopus citations

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 neurodegener-ative 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.

Original languageEnglish (US)
Article numberArticle 192
JournalFrontiers in Genetics
Volume3
Issue numberSEP
DOIs
StatePublished - 2012

Keywords

  • ALS-PDC
  • Alzheimer disease
  • Amyotrophic lateral sclerosis
  • BMAA
  • Colon cancer
  • DNA damage
  • Formaldehyde
  • Methylazoxymethanol

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Genetics(clinical)

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