Cofilin hyperphosphorylation triggers TDP-43 pathology in sporadic amyotrophic lateral sclerosis.

Cofilin is hyperphosphorylated at Ser3 in sporadic ALS and TDP-43 disease models, and this is linked to increased F-actin and downstream TDP-43 pathology.

• Why it matters: TDP-43 pathology is common in ALS, but mechanisms that trigger its cytoplasmic mislocalization, inclusions, and fragmentation are not well defined, limiting therapeutic target discovery.
• What they did: The study measured cofilin phosphorylation and actin dynamics in post-mortem spinal cord from sporadic ALS patients, in TDP-43 rNLS8 transgenic mice, and in NSC-34 cells expressing cytoplasmic TDP-43; it also stabilized F-actin pharmacologically and used a non-phosphorylatable cofilin S3A peptide (MAAGVAVSDGVIKVFN).
• The result: Mimicking cofilin hyperphosphorylation via F-actin stabilization induced cytoplasmic mislocalization, inclusion formation, hyperphosphorylation, fragmentation, and stress granule recruitment, while S3A peptide treatment prevented TDP-43 pathology and apoptosis.

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