MARK2 regulates C9orf72 repeat–associated non-AUG translation

TL;DR

This study identifies MARK2 as a key regulator of harmful protein production linked to a genetic mutation causing neurodegenerative diseases.

Contribution

The novel finding is that MARK2 promotes non-AUG translation of C9orf72 repeats under proteotoxic stress.

Findings

MARK2 is a key eIF2α kinase that enhances RAN translation under proteotoxic stress.

Loss of MARK2 suppresses RAN translation and provides neuroprotection in disease models.

MARK2 signaling is upregulated in C9-ALS patient tissues.

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 translation in reporter cells, patient-derived neurons, and a mouse model and confers neuroprotection under proteotoxic conditions. These findings position MARK2 as a critical stress-sensing cytosolic regulator that promotes repeat-associated noncanonical translation and associated toxicity.

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