FDA-approved PDE4 inhibitors alleviate the dominant toxicity of ALS-FTD-associated CHCHD10S59L by reducing the PINK1/Parkin pathway

Background: Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10 (CHCHD10) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing CHCHD10^S59L, and human cell models expressing CHCHD10^S59L, we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10^S59L. Evidences using in vitro, in vivo genetic, and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10^S59L-induced diseases.

Methods: An in vivo human Cell Culture and in vivo Drosophila models expressing CHCHD10^S59L mutant were utilized in this study to evaluate the effect of PDE4 inhibitors in PINK-parkin mediated cytotoxicity through immunohistochemical and seahorse assays. Data were analysed using one-way ANOVA and post-hoc Dunnett's test for statistical significance.

Results: We investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10^S59L-induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10^S59L-induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H^S81L. Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream Mitophagy induced by CHCHD10^S59L.

Conclusion: These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10^S59L-induced ALS-FTD and possibly Other related diseases, and that disease treatment with PDE4 inhibitors should include careful consideration of the PINK1/Parkin pathway, as it is generally recognized as a protective pathway.

ALS-FTD; CHCHD10; PDE4; PINK1; cAMP-PKA.