The cycad genotoxin methylazoxymethanol, linked to Guam ALS/PDC, induces transcriptional mutagenesis

Excerpt

Guam amyotrophic lateral sclerosis/parkinsonism–dementia complex (ALS/PDC) is a rare neurodegenerative disorder with high prevalence among the native Chamorro population of Guam (Mariana Islands) [1‐3]. ALS/PDC presents clinically as progressive motor neuron disease (resembling classic ALS), parkinsonism with dementia, or a combination of both. At the neuropathological level, ALS/PDC is characterized by tau-dominant multiple proteinopathy (Fig. 1) (an overview of neuropathology can be found in [4]). The etiology of ALS/PDC is unclear, although involvement of both genetic and environmental factors has been suggested. The prevalence of ALS/PDC has declined dramatically in Guam, coincident with rapid westernization [5, 6]. Additionally, migration studies indicate that disease risk is increased after prolonged residence in the geographic cluster [7]. These findings hint at an important role for environmental or lifestyle factors in the disease. Recent whole-genome sequencing (WGS) analysis of postmortem brain and spinal cord tissues from ALS/PDC cases did not find evidence for neurogenetic causes (Additional File 1) and results of cryogenic electron microscopy analysis of tau filaments from ALS/PDC cases are in line with an environmental etiologic hypothesis [8]. There is great interest in understanding the cause of ALS/PDC in Guam, because insight into its origins may also yield clues as to the cause of common neurodegenerative diseases throughout the world [9, 10].

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