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MARK2 regulates C9orf72 repeat-associated non-AUG translation.

Yu-Ning Lu1, Xiangning Li1, Lindsey Hayes2

  • 1Department of Biochemistry and Molecular Biology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205.

Proceedings of the National Academy of Sciences of the United States of America
|November 13, 2025
PubMed
Summary
This summary is machine-generated.

Microtubule affinity-regulating kinase 2 (MARK2) enhances repeat-associated non-AUG (RAN) translation, producing toxic proteins linked to neurodegenerative diseases like C9-ALS/FTD. Inhibiting MARK2 offers neuroprotection against this toxicity.

Keywords:
MARK2eIF2αintegrated stress response

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Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Protein homeostasis is crucial for cellular health and disease prevention.
  • Repeat-associated non-AUG (RAN) translation of GGGGCC repeats in C9orf72 generates dipeptide repeat (DPR) proteins, implicated in C9-ALS/FTD.
  • Mechanisms driving this noncanonical translation are not fully understood.

Purpose of the Study:

  • To identify key regulators of RAN translation under proteotoxic stress.
  • To investigate the role of MARK2-eIF2α signaling in C9-ALS/FTD pathogenesis.
  • To evaluate MARK2 inhibition as a therapeutic strategy for neuroprotection.

Main Methods:

  • Utilized reporter cell systems to study RAN translation.
  • Employed patient-derived neurons and a mouse model of C9-ALS/FTD.
  • Assessed the impact of MARK2 inhibition on RAN translation and proteotoxicity.

Main Results:

  • Identified MARK2 as a crucial eIF2α kinase that promotes RAN translation.
  • Demonstrated MARK2-eIF2α signaling activation by misfolded proteins (DPRs, TDP-43) in C9-ALS patient tissues.
  • Showed that MARK2 loss significantly suppresses RAN translation and confers neuroprotection.

Conclusions:

  • MARK2 acts as a critical stress-sensing cytosolic regulator.
  • MARK2 promotes repeat-associated noncanonical translation and associated cellular toxicity.
  • Targeting MARK2 presents a potential therapeutic avenue for C9-ALS/FTD and related disorders.