MARK2 regulates C9orf72 repeat-associated non-AUG translation.

ABSTRACT: Protein homeostasis is exquisitely regulated through processes involving protein synthesis essential for cellular health and disease prevention. Repeat-associated non-AUG (RAN) translation at expanded GGGGCC repeats in the C9orf72 gene produces dipeptide repeat (DPR) proteins that are implicated in amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). However, the mechanisms promoting this noncanonical translation remain incompletely understood. Here, we identify microtubule affinity-regulating kinase 2 (MARK2) as a key eIF2α kinase that enhances RAN translation under proteotoxic stress. We show that MARK2-eIF2α signaling, activated by misfolded proteins including DPRs and TDP-43, is upregulated in C9-ALS patient tissues. Loss of MARK2 significantly suppresses RAN

SUBMITTER: Lu YN 

PROVIDER: S-EPMC12646204 | biostudies-literature | 2025 Nov

REPOSITORIES: biostudies-literature