FDA-approved PDE4 inhibitors alleviate the dominant toxicity of ALS-FTD-associated CHCHD10S59L in Drosophila and human cells

Mutations in CHCHD10 are a genetic cause of ALS-FTD. In our previous studies using <i>Drosophila</i> expressing C2C10H^S81L and human cells expressing CHCHD10^S59L, we found that the aberrant activation of the PINK1/Parkin pathway drives cellular toxicity, and pseudo-substrate inhibitors of PINK1 or mitofusin-2 agonists can mitigate these effects. Evidence from <i>in vitro</i>, <i>in vivo</i>, and chemical approaches supports PINK1 inhibition as a promising strategy for CHCHD10^S59L-associated disease. Here, we show that FDA-approved PDE4 inhibitors significantly reduce CHCHD10^S59L-induced mitochondrial morphological and functional defects in both human cells and <i>Drosophila</i>. These protective effects occur through a cAMP/PKA-dependent mechanism, indicating that elevated cAMP signaling attenuates aberrant PINK1/Parkin activation. Moreover, forskolin combined with PDE4 inhibitors synergistically decreases mitochondrial toxicity at lower concentrations. Together, our findings suggest that clinically available PDE4 inhibitors could be repurposed for CHCHD10^S59L-linked ALS-FTD, while emphasizing the need to carefully consider the effects of the PINK1/Parkin pathway, as it is generally recognized as a protective pathway.