What is it about?
In diseases like ALS and FTD caused by the C9orf72 gene, toxic proteins called dipeptide repeat (DPR) proteins are produced through an abnormal process. This study identified what triggers this process: a protein called microtubule affinity-regulating kinase 2 (MARK2). MARK2 acts like a stress alarm inside the cell. When harmful proteins, including the toxic DPRs themselves, begin to accumulate, MARK2 becomes activated. Once activated, it turns on a specific pathway that speeds up the production of even more toxic DPR proteins. This creates a dangerous self-perpetuating cycle observed in patient tissue samples and in lab models. Importantly, when scientists inhibited the activity of MARK2, the amount of toxic DPRs was significantly reduced, and patient-derived nerve cells survived better. These findings suggest that targeting MARK2 could be a very promising new approach to treating ALS and FTD.
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Why is it important?
Scientists have long known that toxic DPR proteins contribute to neuron death in C9orf72 ALS and FTD, but they did not know what actually triggers or accelerates their production. Our findings identifying MARK2 as the driver finally pinpoint the mechanism behind this harmful process. Even more importantly, when MARK2 is blocked, the toxic proteins drop dramatically, and nerve cells survive better. This makes MARK2 maybe as a druggable target for slow or disease progression.
Perspectives
Our laboratory has identified MARK2 as the critical stress sensor and driver of toxicity in C9orf72-associated ALS/FTD. MARK2 activates the eIF2α pathway, significantly boosting RAN translation and the production of toxic DPR proteins. Misfolded proteins, including DPRs themselves, create a harmful self-amplifying loop via MARK2, which is highly active in patient tissues. Crucially, blocking MARK2 in patient neurons and mouse models dramatically reduces DPRs and protects nerve cells, establishing MARK2 as a highly promising therapeutic target to slow disease progression.
YuNing Lu
Johns Hopkins University
Read the Original
This page is a summary of: MARK2 regulates C9orf72 repeat–associated non-AUG translation, Proceedings of the National Academy of Sciences, November 2025, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2514182122.
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