Abstract / Summary
Abstract Phosphodiesterase 4 (PDE4) plays a crucial role in the central nervous system (CNS), where it tightly regulates intracellular cyclic adenosine monophosphate (cAMP) levels. Dysregulation of PDE4 activity and cAMP homeostasis has been implicated in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mechanistically, PDE4 inhibition exerts anti‑inflammatory and neuroprotective effects by increasing cAMP accumulation and subsequently activating protein kinase A (PKA), thus representing a promising therapeutic strategy to counteract ALS. However, a major limitation lies in the presence of multiple PDE4 subtypes and isoforms, for which highly selective inhibitors are still lacking. Here, for the first time, we quantify the mRNA expression PDE4 isoforms in the spinal cord, motor cortex, and hind limb muscles of transgenic mice carrying a superoxide dismutase 1 mutation (SOD1 G93A) across disease progression, from presymptomatic to late symptomatic stages, also considering potential sex‑dependent differences. This analysis reveals a marked imbalance in PDE4 isoform expression across tissues, highlighting a subset of mRNAs (PDE4D8 and PDE4A11) that are upregulated in ALS, while others, including PDE4A1, PDE4B1, PDE4B2, PDE4B4, PDE4B5, PDE4D3, and PDE4D7 are downregulated. Hind limb muscles display a robust disease-related alteration pattern, further supporting a peripheral implication of specific PDE4 isoforms' dysregulation. This scenario may explain why the pan-PDE4 inhibitors used so far have failed to produce robust therapeutic benefits in ALS and, conversely, it strengthens the rationale that selectively targeting the isoforms specifically upregulated in the disease could lead to more pronounced therapeutic improvements. No significant sex-related differences have been detected. Highlights SOD1 G93A tissues show a complex PDE4 isoform imbalance, with distinct up-and down-regulation. PDE4D8 and PDE4A11 are upregulated, revealing disease-specific therapeutic targets. Pan-PDE4 inhibitors may fail in ALS; isoform-selective strategies could improve treatment. Selective PDE4 isoform modulation could enhance neuroprotection beyond current inhibitors.