PPM1A dysfunction aggravates DPN pathology through NF-κB/NLRP3/p-tau axis involving Schwann cell/DRG neuron crosstalk

Diabetic peripheral neuropathy (DPN) is a severe diabetic complication with complex pathogenesis. Hyperphosphorylation of tau (p-tau) and neuroinflammation are tightly associated with DPN pathology, although the underlying mechanisms remain obscure. Phosphoproteomics assay with biological verification was performed against the sciatic nerve (SN) tissues from DPN patients and normal individuals to explore the key phosphoprotein(s) involved in DPN pathology. Based on these findings, biological assays including in vivo phosphoprotein-knockdown were then carried out to verify the determined phosphoprotein-mediated mechanisms in DPN pathology against the SN tissues/dorsal root ganglion (DRG) of the model mice. Protein phosphatase Mg²⁺/Mn²⁺ dependent 1 A (PPM1A) enzyme activity was abnormally reduced in both DPN patients and model mice. Treatment with Miltefosine (MF), a PPM1A activator, effectively improved the DPN-like pathology in mice. PPM1A dysfunction aggravates DPN pathology through NF-κB/NLRP3/p-tau axis involving Schwann cell/DRG neuron crosstalk. Our results highlight the close linkage of PPM1A dysfunction to DPN pathology and suggest that pharmacological activation of PPM1A is a potential therapeutic tactic for DPN, while MF shows promise as a valuable drug lead compound against DPN.