. 2024 Feb 21;12(1):30.

doi: 10.1186/s40478-024-01725-y.

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

Bert M Verheijen^{1

2}, Claire Chung³, Ben Thompson⁴, Hyunjin Kim⁵, Asa Nakahara⁶, Jasper J Anink⁷, James D Mills^{7

8

9}; NYGC ALS Consortium; Jeong H Lee⁴, Eleonora Aronica⁷, Kiyomitsu Oyanagi¹⁰, Akiyoshi Kakita⁶, Jean-Francois Gout¹¹, Marc Vermulst³

Collaborators, Affiliations

Collaborators

NYGC ALS Consortium:
Hemali Phatnani, Justin Kwan, Dhruv Sareen, James R Broach, Zachary Simmons, Ximena Arcila-Londono, Edward B Lee, Vivianna M Van Deerlin, Neil A Shneider, Ernest Fraenkel, Lyle W Ostrow, Frank Baas, Noah Zaitlen, James D Berry, Andrea Malaspina, Pietro Fratta, Gregory A Cox, Leslie M Thompson, Steve Finkbeiner, Efthimios Dardiotis, Timothy M Miller, Siddharthan Chandran, Suvankar Pal, Eran Hornstein, Daniel J MacGowan, Terry Heiman-Patterson, Molly G Hammell, Nikolaos A Patsopoulos, Oleg Butovsky, Joshua Dubnau, Avindra Nath, Robert Bowser, Matthew Harms, Eleonora Aronica, Mary Poss, Jennifer Phillips-Cremins, John Crary, Nazem Atassi, Dale J Lange, Darius J Adams, Leonidas Stefanis, Marc Gotkine, Robert H Baloh, Suma Babu, Towfique Raj, Sabrina Paganoni, Ophir Shalem, Colin Smith, Bin Zhang, Brent Harris, University Of Maryland Brain And Tissue Bank And Nih NeuroBioBank, Iris Broce, Vivian Drory, John Ravits, Corey McMillan, Vilas Menon, Lani Wu, Steven Altschuler, Yossef Lerner, Rita Sattler, Kendall Van Keuren-Jensen, Orit Rozenblatt-Rosen, Kerstin Lindblad-Toh, Katharine Nicholson, Peter Gregersen, Jeong-Ho Lee, Maze Therapeutics, Bristol-Myers Squibb, Sulev Koks, Stephen Muljo, Bryan J Traynor, Pfizer, Regeneron, Insitro

Affiliations

¹ School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA. l.m.verheijen1@gmail.com.
² Department of Neuroscience, Maastricht University, Maastricht, The Netherlands. l.m.verheijen1@gmail.com.
³ School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA.
⁴ Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
⁵ Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
⁶ Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan.
⁷ Department of Neuropathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands.
⁸ Department of Clinical and Experimental Epilepsy, University College London Queen Square Institute of Neurology, London, WC1N 3BG, UK.
⁹ Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ, UK.
¹⁰ Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
¹¹ Department of Biological Sciences, Mississippi State University, Mississippi State, MS, 39762, USA.

PMID: 38383591
PMCID: PMC10882831
DOI: 10.1186/s40478-024-01725-y

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

Bert M Verheijen et al. Acta Neuropathol Commun. 2024.

. 2024 Feb 21;12(1):30.

doi: 10.1186/s40478-024-01725-y.

Authors

Collaborators

NYGC ALS Consortium:
Hemali Phatnani, Justin Kwan, Dhruv Sareen, James R Broach, Zachary Simmons, Ximena Arcila-Londono, Edward B Lee, Vivianna M Van Deerlin, Neil A Shneider, Ernest Fraenkel, Lyle W Ostrow, Frank Baas, Noah Zaitlen, James D Berry, Andrea Malaspina, Pietro Fratta, Gregory A Cox, Leslie M Thompson, Steve Finkbeiner, Efthimios Dardiotis, Timothy M Miller, Siddharthan Chandran, Suvankar Pal, Eran Hornstein, Daniel J MacGowan, Terry Heiman-Patterson, Molly G Hammell, Nikolaos A Patsopoulos, Oleg Butovsky, Joshua Dubnau, Avindra Nath, Robert Bowser, Matthew Harms, Eleonora Aronica, Mary Poss, Jennifer Phillips-Cremins, John Crary, Nazem Atassi, Dale J Lange, Darius J Adams, Leonidas Stefanis, Marc Gotkine, Robert H Baloh, Suma Babu, Towfique Raj, Sabrina Paganoni, Ophir Shalem, Colin Smith, Bin Zhang, Brent Harris, University Of Maryland Brain And Tissue Bank And Nih NeuroBioBank, Iris Broce, Vivian Drory, John Ravits, Corey McMillan, Vilas Menon, Lani Wu, Steven Altschuler, Yossef Lerner, Rita Sattler, Kendall Van Keuren-Jensen, Orit Rozenblatt-Rosen, Kerstin Lindblad-Toh, Katharine Nicholson, Peter Gregersen, Jeong-Ho Lee, Maze Therapeutics, Bristol-Myers Squibb, Sulev Koks, Stephen Muljo, Bryan J Traynor, Pfizer, Regeneron, Insitro

Affiliations

¹ School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA. l.m.verheijen1@gmail.com.
² Department of Neuroscience, Maastricht University, Maastricht, The Netherlands. l.m.verheijen1@gmail.com.
³ School of Gerontology, University of Southern California, Los Angeles, CA, 90089, USA.
⁴ Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Republic of Korea.
⁵ Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
⁶ Department of Pathology, Brain Research Institute, Niigata University, Niigata, Japan.
⁷ Department of Neuropathology, Amsterdam UMC, University of Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands.
⁸ Department of Clinical and Experimental Epilepsy, University College London Queen Square Institute of Neurology, London, WC1N 3BG, UK.
⁹ Chalfont Centre for Epilepsy, Chalfont St Peter, SL9 0RJ, UK.
¹⁰ Division of Neuropathology, Department of Brain Disease Research, Shinshu University School of Medicine, Matsumoto, Nagano, Japan.
¹¹ Department of Biological Sciences, Mississippi State University, Mississippi State, MS, 39762, USA.

PMID: 38383591
PMCID: PMC10882831
DOI: 10.1186/s40478-024-01725-y

No abstract available

Keywords: DNA damage; Environmental toxin; Guam amyotrophic lateral sclerosis/parkinsonism–dementia complex; O6-mG; Transcriptional mutagenesis.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**Fig. 1**
Phosphorylated tau (pTau) aggregates in Guam ALS/PDC tissues. pTau cytoplasmic inclusions in brain (A–C) and anterior horn of the spinal cord (D-F) in Guam ALS/PDC cases (AT8, Innogenetics). A–C and **D–F** show increasing magnifications of representative immunostained tissue sections. pTau aggregates in brain and spinal cord are well-known pathological hallmarks of ALS/PDC and were used for diagnosis of cases included in Additional File 1. Tissue sections correspond to Guam PDC subject #3 (**A–C**) and #1 (**D–F**) from [8]

**Fig. 2**
Methylazoxymethanol (MAM) exposure induces transcriptional mutagenesis in neural stem cells. A Overview of the experiment. Mouse primary hippocampal neural stem cells (NSCs) were cultured in quiescence medium for 3 days. Cell cycle arrest was validated by Ki-67 staining. Next, quiescent NSCs were treated with 1 mM methylazoxymethanol (MAM) acetate or vehicle (PBS) for 1 h, after which cells were rinsed with PBS and cultured for 16 more hours in quiescence medium. Cells were then collected and used for single-cell RNA-seq experiments. B The error spectrum of RNAPII in MAM-treated NSCs shows an increased C → U error rate as compared to vehicle-treated cells. *P < 0.01, unpaired two-tailed t-test. C MAM treatment results in transcripts containing identical errors, termed pseudo-alleles for their ability to generate both WT and mutant transcripts. The graph depicts the ratio of mutant:WT mRNAs detected. Only alleles with more than 10% mutant mRNAs are included (MAM-treated replicate #1). D It is proposed that (1) mutant RNAs, which are the result of transcriptional mutagenesis on unrepaired O⁶-methylguanine (O⁶-mG) DNA lesions, could initiate disease by generating toxic molecules, e.g., misfolded proteins that act as proteopathic seeds. Additionally, (2) an overall increase in the number of erroneous RNAs could overwhelm the cellular protein quality control machinery, potentiating proteotoxic stress phenotypes by impairing the clearance of toxic proteins. Lastly, (3) transcription errors could promote the transition of stressed cells to a dysfunctional state through various mechanisms

See this image and copyright information in PMC

References

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

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

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