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Modifying the m6A brain methylome by ALKBH5-mediated demethylation: a new contender for synaptic tagging

Martinez De La Cruz, Braulio; Markus, Robert; Malla, Sunir; Haig, Maria Isabel; Gell, Chris; Sang, Fei; Bellows, Eleanor; Sherif, Mahmoud Awad; McLean, Denise; Lourdusamy, Anbarasu; Self, Tim; Bodi, Zsuzsanna; Smith, Stuart; Fay, Michael; Macdonald, Ian A.; Fray, Rupert; Knight, Helen Miranda


Braulio Martinez De La Cruz

Robert Markus

Sunir Malla

Maria Isabel Haig

Chris Gell

Fei Sang

Mahmoud Awad Sherif

Denise McLean

Tim Self

Zsuzsanna Bodi

Clinical Associate Professor

Ian A. Macdonald

Professor of Epitranscriptomics


Synaptic plasticity processes, which underlie learning and memory formation, require RNA to be translated local to synapses. The synaptic tagging hypothesis has previously been proposed to explain how mRNAs are available at specific activated synapses. However how RNA is regulated, and which transcripts are silenced or processed as part of the tagging process is still unknown. Modification of RNA by N6-methyladenosine (m6A/m) influences the cellular fate of mRNA. Here, by advanced microscopy, we showed that m6A demethylation by the eraser protein ALKBH5 occurs at active synaptic ribosomes and at synapses during short term plasticity. We demonstrated that at activated glutamatergic post-synaptic sites, both the YTHDF1 and YTHDF3 reader and the ALKBH5 eraser proteins increase in co-localisation to m6A-modified RNAs; but only the readers showed high co-localisation to modified RNAs during late-stage plasticity. The YTHDF1 and YTHFDF3 readers also exhibited differential roles during synaptic maturation suggesting that temporal and subcellular abundance may determine specific function. m6A-sequencing of human parahippocampus brain tissue revealed distinct white and grey matter m6A methylome profiles indicating that cellular context is a fundamental factor dictating regulated pathways. However, in both neuronal and glial cell-rich tissue, m6A effector proteins are themselves modified and m6A epitranscriptional and posttranslational modification processes coregulate protein cascades. We hypothesise that the availability m6A effector protein machinery in conjunction with RNA modification, may be important in the formation of condensed synaptic nanodomain assemblies through liquid-liquid phase separation. Our findings support that m6A demethylation by ALKBH5 is an intrinsic component of the synaptic tagging hypothesis and a molecular switch which leads to alterations in the RNA methylome, synaptic dysfunction and potentially reversible disease states.


Martinez De La Cruz, B., Markus, R., Malla, S., Haig, M. I., Gell, C., Sang, F., …Knight, H. M. (2021). Modifying the m6A brain methylome by ALKBH5-mediated demethylation: a new contender for synaptic tagging. Molecular Psychiatry, 26(12), 7141-7153.

Journal Article Type Article
Acceptance Date Aug 28, 2021
Online Publication Date Oct 19, 2021
Publication Date 2021-12
Deposit Date Sep 24, 2021
Publicly Available Date Oct 19, 2021
Journal Molecular Psychiatry
Print ISSN 1359-4184
Electronic ISSN 1476-5578
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 26
Issue 12
Pages 7141-7153
Public URL
Publisher URL