Lysine deacetylation inhibition reverses TDP-43 mislocalization and in combination with arimoclomol ameliorates neuromuscular pathology
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Background
Cytoplasmic inclusions containing TAR DNA-binding protein 43 kDa (TDP-43) are recognized as a major pathological feature of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, but more recently have been associated with several neurodegenerative conditions. Cyclophilin A (PPIA), a foldase and molecular chaperone, interacts with TDP-43 and influences its aggregation and function. The interaction between PPIA and TDP-43 is facilitated by PPIA Lys-acetylation, which is reduced in peripheral blood mononuclear cells (PBMCs) of ALS patients showing signs of TDP-43 proteinopathy. In this study, we investigated the effect of lysine deacetylation inhibition to uncover the underlying mechanisms of TDP-43 proteinopathy in relation to PPIA acetylation, and to identify new therapeutic avenues.
Methods
Through a screening of histone deacetylase (HDAC) inhibitors in a cellular model of TDP-43 proteinopathy, we identified vorinostat/SAHA, capable of increasing PPIA acetylation, as the most effective in reversing TDP-43 mislocalization. We confirmed its effect in PBMCs from ALS patients. Next, we explored its impact on proteinopathy and PPIA acetylation in a severe and fast-progressing TDP-43-overexpressing mouse model (Thy1-hTDP-43), using several molecular biomarkers as outcome measures, including neurofilament light chain (NfL) in plasma.
Results
Thy1-hTDP-43 mice treated with SAHA showed a delayed onset of TDP-43 pathology, associated with PPIA nucleus-cytoplasm redistribution, lower levels of neurodegeneration and neuroinflammation markers, and improved neuromuscular function markers. However, over time, the broad-spectrum inhibitor SAHA was unable to counteract the two-fold overexpression of TDP-43 and led to the accumulation of side effects. When combined with the heat shock protein (HSP) co-inducer arimoclomol, a mitigation of the neurodegeneration was sustained. Moreover, a synergistic effect was observed in periphery, greatly enhancing tubulin acetylation and reducing pTDP-43 accumulation in the sciatic nerve. This resulted in a more pronounced reduction of NfL in plasma and acetylcholine receptor (AChR) γ-subunit expression in gastrocnemius muscle, indicating reduced axonal transport impairment and muscle denervation.
Conclusions
This study suggests that HDAC inhibition, by increasing acetylated PPIA, could be beneficial in restoring TDP-43 localization and function. The combination of lysine deacetylation inhibition and HSP induction shows a synergistic effect in vivo and has potential as a therapeutic approach for patients.
