Palmitoyl Acyltransferase Zdhhc17 Promotes Functional Recovery After Spinal Cord Injury by Targeting the Nuclear Transport Factors Kpna2 and Ipo9

ABSTRACT In adult mammals, poor functional recovery after spinal cord injury (SCI) is largely due to the very limited capacity to reconstruct damaged neural connections together with neuronal loss. Here, we identify the neuroprotective role of Zdhhc17 as a palmitoyl acyltransferase (PAT) following SCI. Neuron‑specific Zdhhc17 overexpression in vitro and in vivo markedly enhances axon regeneration and functional recovery after SCI in a PAT‐activity‐dependent manner. Interactome and palmitoylation analyses in cortical neurons identify the karyopherins Kpna2 and Ipo9 as previously unrecognized Zdhhc17 substrates. SCI markedly reduces Kpna2 and Ipo9 protein levels, whereas Zdhhc17‑mediated palmitoylation stabilizes them by suppressing their ubiquitin‑dependent degradation. Functionally, neuronal overexpression of Kpna2 or Ipo9 mimics the therapeutic effects of Zdhhc17, and co‑expression of Zdhhc17 with Ipo9, but not Kpna2, further augments SCI repair. Using H 2 O 2 ‑induced oxidative stress and glutamate‑induced excitotoxicity models, we further show that Zdhhc17 promotes neuronal survival and activates transcription of intrinsic pro‑regenerative genes after injury. These findings suggest that the Zdhhc17‐Kpna2/Ipo9 axis is a novel pharmacological target for SCI treatment.