Loss of APOBEC1 disrupts RNA editing homeostasis and accelerates prion disease progression.

Abstract

Background: RNA editing is an epitranscriptomic mechanism that shapes transcriptome diversity and fine-tunes neuronal function. While adenosine-to-inosine (A-to-I) editing by ADAR enzymes has been extensively studied in neurodegenerative disorders, the role of cytidine-to-uridine (C-to-U) editing catalyzed by APOBEC1 remains largely unexplored.

Methods: We investigated the impact of APOBEC1 on RNA editing homeostasis and prion disease progression using complementary in vitro and in vivo models. Global RNA editing and gene expression profiles were established in non-infected N2A and prion-infected sc-N2A murine neuroblastoma cells, under control conditions or following APOBEC1 depletion. APOBEC1 was silenced by shRNA-mediated knockdown to assess its regulatory contribution. In vivo disease progression was assessed in Apobec1 knockout mice subjected to RML prion infection to evaluate survival outcomes.

Results: Prion infection was associated with a global increase in RNA editing and an expanded repertoire of edited transcripts in sc-N2A cells. APOBEC1 depletion markedly reduced the overall editing levels, affecting both A-to-I and C-to-U editing events, reshaping editing patterns in transcripts associated with RNA and protein transport, cellular stress responses, synaptic signaling, and neuroimmune interactions. Consistently, Apobec1 KO mice exhibited accelerated body weight loss and significantly shortened survival following RML prion challenge.

Conclusions: These findings support APOBEC1 as a contributor to RNA editing homeostasis and suggest that APOBEC1 loss reduces resilience to prion-induced neurodegenerative stress. APOBEC1 deficiency was associated with altered editome profiles in prion-infected cells and accelerated disease progression in the RML prion model.