TDP-43 is an RNA-binding protein and a biomarker of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration.  Here, we identify lysine acetylation as a novel post-translational modification controlling TDP-43 function and aggregation.

From a large scale identification of acetylation sites data (a global proteome contain 1,750 proteins), we found two acetylation sites (Lys-145 and Lys-192) on TDP-43. And then, confirmed the modification by pan-acetylation antibody and mass spectrum.

As TDP-43 binds to 6,000 genes and regulates target RNAs that are essential for proper neuronal development and synaptic function, given that the acetylated lysines are located within the RRM domains, we guess the acetylation may affect its RNA binding activity. The double mutant (TDP-K145Q or TDP-2KQ), showed a 50–65% decrease in RNA binding. TDP-43 acetylation mimics (K-Q) to the cytoplasm increased P-409/410 levels in insoluble fractions.

Co-expression of WT HDAC6, but not a catalytically inactive H803A mutant, together with CBP was sufficient to deacetylate cytoplasmic TDP-43 under normal cellular conditions.

We also show acetylated TDP-43 lesions are found in ALS patient spinal cord, indicating that aberrant TDP-43 acetylation and loss of RNA binding.

The identification of a reversible TDP-43 acetylation switch provides a novel framework to understand both physiological and pathological TDP-43 functions, which could lead to targeted therapies against ALS.