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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.
Summary
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.
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.
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