ABSTRACT
Dysregulated RNA metabolism is a significant feature of Alzheimer’s 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.
HIGHLIGHTS
With age, the number of m6A sites increases among Control cases (lacking AD pathology) but remains unchanged in AD cases.
Transcripts are globally hypomethylated in AD cases.
Hypomethylation is linked to decreased mRNA expression of transcripts related to synaptic and proteostatic function in AD.
3’UTR-localized m6A sites lack typical association with transcript metabolism of GABRA1 in AD.
Competing Interest Statement
BW is Co-founder and CSO of Aquinnah Pharmaceuticals Inc.
Footnotes
Title and abstract edited to include "m6A".
Funder Information Declared
