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

## TL;DR

FDA-approved PDE4 inhibitors reduce mitochondrial damage caused by a CHCHD10 mutation linked to ALS-FTD in both human cells and fruit flies.

## Contribution

FDA-approved PDE4 inhibitors are shown to alleviate CHCHD10S59L toxicity via a cAMP/PKA-dependent mechanism involving the PINK1/Parkin pathway.

## Key findings

- PDE4 inhibitors reduce mitochondrial defects caused by CHCHD10S59L in human cells and Drosophila.
- The protective effects of PDE4 inhibitors depend on cAMP/PKA signaling and involve the PINK1/Parkin pathway.
- Low-dose forskolin combined with PDE4 inhibitors synergistically reduces mitochondrial toxicity.

## Abstract

Mutations in CHCHD10 are a genetic cause of ALS-FTD. In our previous studies using Drosophila expressing C2C10HS81L and human cells expressing CHCHD10S59L, 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 in vitro, in vivo, and chemical approaches supports PINK1 inhibition as a promising strategy for CHCHD10S59L-associated disease. Here, we show that FDA-approved PDE4 inhibitors significantly reduce CHCHD10S59L-induced mitochondrial morphological and functional defects in both human cells and Drosophila. 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 CHCHD10S59L-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.

•PDE4 inhibitors reduce CHCHD10S59L mitochondrial defects•Protective effects are cAMP/PKA dependent and act via PINK-Parkin pathway•Low-doses of forskolin and PDE4 inhibitor provide synergistic boost•PDE4 inhibitors can be repurposed for ALS-FTD via PINK1/Parkin pathway

PDE4 inhibitors reduce CHCHD10S59L mitochondrial defects

Protective effects are cAMP/PKA dependent and act via PINK-Parkin pathway

Low-doses of forskolin and PDE4 inhibitor provide synergistic boost

PDE4 inhibitors can be repurposed for ALS-FTD via PINK1/Parkin pathway

Pharmacology; Entomology; Molecular biology; Neuroscience