Loss of age-associated increase in m6A-modified RNA contributes to GABAergic dysregulation in Alzheimer's disease

Libera, J. L.; Hu, J.; Nguyen, T.-A.; Wang, Z.; van der Spek, S. J. F.; Schult, K.; Dorrian, L.; Majka, J.; Tobunluepop, K.; Puri, S.; Kynshov, A.; Kanaan, N. M.; Nelson, P. T.; Meyer, K.; Hou, L.; Zhang, X.; Wolozin, B.

doi:10.1101/2025.05.02.651974

bioRxiv · 10.1101/2025.05.02.651974

Loss of age-associated increase in m6A-modified RNA contributes to GABAergic dysregulation in Alzheimer's disease

Libera, J. L.·Hu, J.·Nguyen, T.-A.·Wang, Z.·van der Spek, S. J. F.·Schult, K.·Dorrian, L.·Majka, J.·Tobunluepop, K.·Puri, S.·Kynshov, A.·Kanaan, N. M.·Nelson, P. T.·Meyer, K.·Hou, L.·Zhang, X.·Wolozin, B.

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Abstract

Dysregulated RNA metabolism is a significant feature of Alzheimers disease (AD), yet how post-transcriptional RNA modifications like N6-methyladenosine (m6A) are altered in AD is unknown. Here, we performed deamination adjacent to RNA modification targets (DART-seq) on human dorsolateral prefrontal cortices to assess changes in m6A with nucleotide resolution. In non-AD brains, m6A sites increased with age, predominantly within the 3'UTR of transcripts encoding tripartite synapse proteins. In contrast, AD brains lost the age-associated m6A site increase and exhibited global hypomethylation of transcripts, including MAPT and APP. Hypomethylated genes involved with GABAergic signaling, glutamate transport, and ubiquitin-mediated proteolysis exhibited reduced expression, connecting m6A to synaptic excitotoxicity and disrupted proteostasis in AD. Site-specific m6A levels were linked with GABRA1 expression and protein levels, but this relationship was abolished in AD. Our findings provide insight into post-transcriptional mechanisms of dysregulated RNA metabolism in AD that are related to aging and GABAergic regulation. HIGHLIGHTSO_LIWith age, the number of m6A sites increases among Control cases (lacking AD pathology) but remains unchanged in AD cases. C_LIO_LITranscripts are globally hypomethylated in AD cases. C_LIO_LIHypomethylation is linked to decreased mRNA expression of transcripts related to synaptic and proteostatic function in AD. C_LIO_LI3UTR-localized m6A sites lack typical association with transcript metabolism of GABRA1 in AD. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=196 SRC="FIGDIR/small/651974v3_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@995c55org.highwire.dtl.DTLVardef@7d0619org.highwire.dtl.DTLVardef@1b6a20org.highwire.dtl.DTLVardef@1d47dce_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Libera, J. L., Hu, J., Nguyen, T.-A., Wang, Z., van der Spek, S. J. F., Schult, K., Dorrian, L., Majka, J., Tobunluepop, K., Puri, S., Kynshov, A., Kanaan, N. M., Nelson, P. T., Meyer, K., Hou, L., Zhang, X., Wolozin, B.. 2025-05-06. Loss of age-associated increase in m6A-modified RNA contributes to GABAergic dysregulation in Alzheimer's disease. https://doi.org/10.1101/2025.05.02.651974

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