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

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 e...

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Published in:Acta neuropathologica communications 2024-02, Vol.12 (1), p.30-5, Article 30
Main Authors: Verheijen, Bert M, Chung, Claire, Thompson, Ben, Kim, Hyunjin, Nakahara, Asa, Anink, Jasper J, Mills, James D, Lee, Jeong H, Aronica, Eleonora, Oyanagi, Kiyomitsu, Kakita, Akiyoshi, Gout, Jean-Francois, Vermulst, Marc
Format: Article
Language:English
Subjects:
Amyotrophic lateral sclerosis
Amyotrophic Lateral Sclerosis - genetics
Dementia
Disease
DNA damage
Environmental toxin
Experiments
Guam
Guam amyotrophic lateral sclerosis/parkinsonism–dementia complex
Humans
Hypotheses
Letter to the Editor
Methylazoxymethanol Acetate - analogs & derivatives
Mutagenesis
Mutagens
Mutation
Neurodegeneration
Neurology
O6-mG
Pathogenesis
Proteins
Toxins
Transcriptional mutagenesis
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Summary: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]. Next, cells were rinsed with PBS to remove MAM from the culturing medium, after which they were allowed to recover in quiescence medium for 16 h. Again, an important consideration is that, as long as DNA damage is not repaired, bursts of transcription on the damaged DNA will result in mutant RNAs that contain an error at the same location as the corresponding damage site. The in vitro experiments with MAM described here should ideally be complemented by other assays, such as DNA damage and mutation detection assays, and should preferably also be extended to human cells (e.g., human induced neurons) and intact animals. Nature 216(5122):1311–1312 Kisby GE, Fry RC, Lasarev MR, Bammler TK, Beyer RP, Churchwell M et al (2011) The cycad genotoxin MAM modulates brain cellular pathways involved in neurodegenerative disease and cancer in a DNA damage-linked manner.
ISSN:2051-5960
2051-5960
DOI:10.1186/s40478-024-01725-y